SU2C's newest Innovative Research Grant recipients were announced at the 2017 Annual Meeting of the American Association for Cancer Research (AACR), SU2C’s Scientific Partner. Awards were given to 10 early-career scientists, in a program funded by a grant from Bristol-Myers Squibb Company (BMS), an SU2C Visionary Supporter.
SU2C's newest Innovative Research Grant recipients were awarded on April 18th, 2016. This third round of high-risk, high-reward IRG grants support cutting-edge cancer research from early-career scientists who might not receive funding through traditional channels.
SU2C's newest Innovative Research Grant recipients were awarded on April 4th, 2011. This second round of high-risk, high-reward IRG grants support cutting-edge cancer research from early-career scientists who might not receive funding through traditional channels. Take a look at the novel ideas presented by this year's 13 recipients and find out how their projects have a strong potential to impact patient care.
SU2C's first thirteen Innovative Research Grants, awarded in December of 2009, support cutting-edge cancer research that might not receive funding through traditional channels. Innovative Research Grants support early-career scientists with novel ideas that have a strong potential to impact patient care - projects that are high-risk but could also be high-impact.
SU2C's Innovative Research Grants (IRGs) support cutting-edge cancer research that might not receive funding through traditional channels. IRGs support early-career scientists with novel ideas that have a strong potential to impact patient care - projects that are high-risk but could also be high-impact. To date, we’ve awarded four rounds of IRGs, in 2009, 2011, 2016, and 2017, giving us forty-six very promising early-career researchers.
IRG Recipients at a Glance
Probing EBV-LMP-1’s Transmembrane Activation Domain with Synthetic Peptide
The goal of this project is to demonstrate how the human Epstein-Barr virus (EBV), which infects 90 percent of the world population, contributes to cell survival and cell division.
“We’re definitely trying to help people. Trying to understand why people develop cancer and trying to give them our help for diagnosing cancers early and prevent them from the very beginning.”
Functional Oncogene Identification
Using a novel system that identifies the molecular abnormalities that drive cancer causation and growth directly from patient tumors, this project will make the molecular profiling process faster, more efficient and more precise.
“We want to look in a broad array of different tumor types and try to pull out new oncogene alterations. That’s something that is difficult and it’s high risk, but it’s extremely high reward.”
A Transformative Technology to Capture and Drug New Cancer Targets
This project will bring together multiple fields — chemistry, biology and cancer drug development — to deploy a technology that can rapidly and precisely identify cancer-causing proteins and their malignant interaction sites.
“Our job – and it's truly a quest – is to try to find the Achilles heel of these cancer cells. And there may be more than one Achilles heel, and the only way to find them is to use new technologies. And once we do find them then we can actually get on the path of developing drugs against them.”
Noninvasive Molecular Profiling of Cancer via Tumor-Derived Microparticles
This project will develop a new approach to profiling tumors by capturing and examining “microparticles,” tiny genetic material-containing packets that are emitted by cells in the tumor tissue and circulate in the blood.
“We’re at this point where all of this knowledge that's been accumulated through really painstaking work is about to flip, and about to translate into new therapies, into new tests, and potentially into ways of preventing cancer.”
Modulating Transcription Factor Abnormalities in Pediatric Cancer
This project will target the EWS-FLI protein, the “undruggable” cancer-promoting protein in Ewing sarcoma, screening a library of chemicals for those that induce the gene fingerprint of the inactive EWS-FLI protein to identify potential anti-cancer drugs.
“Our work focuses on new approaches to drug discovery. And so, as such, the hope is that molecules that emerge from the screen might someday actually become clinical drugs that are used in the treatment of patients.”
Genetic Approaches for Next Generation of Breast Cancer Tailored Programs
The goal of this project is to open up a new frontier of targeted therapy development by identifying specific gene functions that only serve the existence of cancer cells, with no benefit to normal cells and healthy tissue.
“Every day I try to be better than I was the last day. I try to learn more than I knew the last day. I would like to provide the clinical community with noble targets so they can give more hope to the patients.”
Endogenous Small Molecules that Regulate Signaling Pathways in Cancer CellsRajat Rohatgi, M.D., Ph.D., Stanford University
This project will identify small molecules that regulate the Hedgehog signaling pathway, which drives the development of a large number of childhood and adult cancers. Dr. Rohatgi's integrative approach will use tools from cell biology and chemistry to find the influential molecules and a new hope in the treatment of a variety of cancers.
“The future of cancer research is going to come from breaking down traditional barriers and approaches to solving problems and not being afraid to embrace concepts from different fields. This project really forces me to think beyond my roles as a biologist and a physician who sees patients.”
Therapeutically Targeting the Epigenome in Aggressive Pediatric Cancers
Dr. Charles M. Roberts designed a model system which will now be used to examine epigenetic pathways in pursuit of therapies that can reverse the non-permanent epigentic effects of losing the SNF5 gene. The loss affects DNA packaging and often results in an extremely lethal pediatric cancer primarily affecting children under 2 years old. Discovery of a method of reversal would translate to hope for these young patients and have far reaching implications for almost every type of cancer.
“Why do I fight this disease? I’m a pediatric oncologist and I see firsthand the devastating effect that this disease can have on children and their families. And there’s nothing more motivating than seeing a child suffering to make me want to do better.”
Identifying Solid Tumor Kinase Fusions via Exon Capture and 454 Sequencing
The uncontrolled cell growth that is a common characteristic of cancer is often compared to a broken switch, as is sometimes the case with thetyrosine kinases (TK), a class of molecular switches controlling cell growth, which can cause cancer when altered, sometimes the result of fusion with cellular protein. Dr. Pao will lead a search for 100 such fusions in lung and breast cancers, offering fresh therapeutic targets based on the model of Gleevec, the highly effective drug which targets a specific alteration in leukemia.
“The government tends to fund more conservative proposals that may not lead to the next breakthrough. SU2C has committed to funding the most innovative grants that can really make a large impact on cancer and cancer outcomes in the next few years.”
Targeting Inhibition of BCL6 for leukemia Stem Cell Eradication
This IRG concentrates on the BCL6 protein—how it influences leukemia at onset and relapse, the protein's relationship to leukemia stem cells, and preliminary development of a new BCL6 inhibitor capable of eliminating dormant leukemia stem cells.
“The key to conquering cancer, if there’s any, and I hope there is, will be collaboration.”
Coupled Genetic and Functional Dissection of Chronic Lymphocytic Leukemia
There are two main challenges to treating chronic lymphocytic leukemia (CLL): predicting the clinical course in a disease that shows many differences across patients, and overcoming the insensitivity of some patient tumors to chemotherapy. There is a need for improved understanding of how disease starts and progresses, which would lead to better predictive markers and potentially more effective (and non-toxic) therapies.
Recent advances in genomic technologies provide a unique opportunity to find the genes and molecular circuits that make tumors grow in CLL. Dr. Wu is sequencing genes from tumor and normal cells from CLL patients. She is examining how genes are expressed in the same patient tumors using gene microarrays. Dr. Wu’s laboratory pioneered the use of silicon-coated nanowires as a method of delivering DNA and RNA to primary CLL and normal B cells, allowing her to genetically manipulate CLL cells for the first time in a high-throughput fashion. Her analysis thus far has identified genes important for CLL, and the nanowires have verified the importance of some of these genes in CLL tumor cells. This project enables Wu to find all the major genes and pathways that control CLL tumor formation. She will use a combination of sequencing technologies with statistical analyses to find the key genes that are important in creating tumors in CLL patients.
In addition, she will determine which genes are good predictors of disease progression. Then, she will use nanowires to place the mutant genes from CLL tumors into normal B cells and see how they affect their behavior. This project will lead to an understanding of the basic reasons why CLL patients develop cancer. The information will help predict progression of disease and provide new strategies for therapy. Her approach can be extended to other tumors, especially leukemias and lymphomas.
“I think advocating for getting novel findings and translating it earlier to the clinic is imperative.”
Framing Therapeutic Opportunities in Tumor-activated Gametogenic Programs
Unlike infectious diseases, cancer is caused by a rewiring of normal molecular systems to produce an uncontrollably dividing cell. This characteristic makes it notoriously difficult to identify therapeutic mechanisms that will target cancer cells, without harming normal tissues.
Tumors, at high frequency, turn on genes that are only normally required for reproduction and not otherwise expressed in an adult lung, heart, brain, etc. If these genes are necessary for tumor cells to survive, they present a tremendous opportunity as therapeutic targets, since they are not required for the function of critical organs. Dr. Whitehurst’s group studies whether the proteins encoded by these genes are required for tumor cells to grow and divide. Her work has revealed that directly inhibiting a subset of these proteins can lead to the selective death of cancer cells, thereby providing a previously unrecognized basis for the design of new cancer therapeutics. Her lab’s mission is to build and expand on this expertise to more broadly evaluate all 105 of the genes that are found in tumors but not in normal adult tissues. Dr. Whitehurst will use a unique large-scale approach to determine which of these genes are most critical for tumor cell survival. Next, she will test if they are required for survival in tumors in animals. Finally, because little is known about how they support growth of tumor cells, she will investigate the ways in which they interact with other proteins to promote the unbridled growth of tumor cells.
Ultimately, this work will present new targets for therapeutic intervention that will selectively destroy tumor cells and leave normal tissues unharmed.
“We have more knowledge than we’ve ever had before, and knowledge is power. Cancer isn’t getting smarter, but we are.”
Developing New Therapeutic Strategies for Soft-tissue Sarcoma
Sarcomas are highly aggressive cancers that arise in connective tissues such as bone, fat and cartilage, as well as in muscles and blood vessels embedded within these tissues. Approximately 12,000 Americans are diagnosed with sarcoma each year. These tumors can occur at any age, but many (e.g. rhabdomyosarcoma) are disproportionately common in children and young adults.
Current sarcoma treatment strategies are often ineffective, particularly with advanced disease, and, sadly, even with the most advanced therapies currently available, one third to one half of sarcoma patients will die from their disease. Dr. Wagers’ lab has developed a novel mouse model of soft-tissue sarcoma in skeletal muscle. This model exploits her lab’s unique ability to isolate discrete subsets of tissue stem cells found normally in the skeletal muscle and the connective tissue surrounding it, and introduces into these cells specific genetic modifications associated with human sarcomas.
Using this model, she found that introduction of a particular combination of modifications into distinct types of tissue stem cells rapidly and reproducibly generates transplantable sarcomas that model particular subtypes of human tumors. By comparing these different tumors, she has identified a small group of genes present at increased levels in both mouse and human sarcomas.
Dr. Wagers hypothesizes that this novel set of sarcoma-induced genes includes new candidate drug targets. She will evaluate a library of drugs that target her identified sarcoma-associated genes, and identify those that prevent or impede sarcoma development, growth or metastasis. These efforts will benefit from synergistic analyses in her established mouse model and an entirely new, humanized system that will allow her to interrogate the efficacy of candidate therapeutics in an appropriate human cell context.
This approach will generate essential pre-clinical data to facilitate clinical translation of candidate pharmaceutical targets identified and validated by our studies. Ultimately, this work will identify new, more effective anti-sarcoma therapies, based on a better understanding of how these cancers arise and grow, provide new insights into the root causes of sarcoma formation, and identify new strategies to cure these aggressive cancers.
“Science is all about discovery, and you can only discover things by coming at it in a new way. We need to approach cancer in every creative way that we possibly can because this is a terribly important problem.”
Inhibiting Innate Resistance to Chemotherapy in Lung Cancer Stem Cells
Lung cancer is projected to remain a leading cause of cancer death for the foreseeable future. The most common form of lung cancer is non-small cell lung cancer (NSCLC). Platinum-based chemotherapy drugs are commonly used to treat NSCLC and other cancers, though treatment with these drugs has limited effect. There is a need to develop new ways to increase the effectiveness of chemotherapy for this disease. Current strategies for developing new drugs for NSCLC rely almost exclusively on testing of candidate agents on established cell lines. A limitation of working with cell lines is that they are usually grown directly on plastic culture dishes in “2D” (growing flat on the plates).
Research over the last decade has demonstrated that this method of culturing cells is very different from the conditions that tumor cells experience in a patient. Sweet-Cordero has developed an approach that incorporates the advantages of mouse models and “3D” culture systems to study cancer, and will use this approach as a platform to identify new ways to make chemotherapy more effective at killing lung tumor cells. Using tumor cells isolated from a well-characterized mouse model of lung cancer in which tumors carry one of the most frequent genetic mutations found in human lung cancer (a gene called Kras), Dr. Alejandro will carry out a screen using a technology called “shRNA,” which allows him to selectively inhibit the action of individual genes. He will test whether loss of specific genes makes cells growing in “3D” more sensitive to chemotherapy. His studies will result in the identification of new targets for drugs that make chemotherapy more effective to treat human lung cancer.
“Innovative proposals sometimes are great ideas, but don't have all of the background data to support them; and in order for them to move forward, they require the funding from forward thinking, innovative groups such as Stand Up 2 Cancer.”
Targeting Sleeping Cancer Cells
Cancer cells of different types have the very strange ability to go to sleep and then eventually wake up. While cancer cells sleep, they are resistant to virtually all currently available forms of treatment. However, we do not understand how highly aggressive cancer cells become dormant. It has proven extremely difficult to study these cells directly in patients and we have lacked suitable model systems to study them in the laboratory.
Dr. Ramaswamy recently made a remarkable observation that has the potential to open this important area for new investigation. He found that highly aggressive cancer cell lines of various types occasionally produce dormant cells. This has enabled the development of methods to identify, isolate and experimentally probe spontaneously arising quiescent cancer cells at the molecular level. Dr. Ramaswamy will use cutting edge genomic, proteomic and computational technologies to identify and validate genetic and protein signaling networks that trigger and maintain cancer cell dormancy. His goal is to develop new diagnostics and drugs based on this insight to prevent cancer cells from becoming dormant or kill them while they sleep.
“I think it’s critical to be continually pushing the envelope. To the degree that one tries new things, you have a better chance of finding new things.”
A Systems Approach to Understanding Tumor Specific Drug Response
Cancer is an individual disease—unique in how it develops and behaves in each patient. The emergence of revolutionary genomic technologies, combined with increased understanding of the molecular basis underlying cancer initiation, has increased the hope that treatment will improve by becoming more targeted and individualized in nature.
Dr. Pe’er’s project elucidates tumor-specific molecular networks, which are the information processing devices of cells. In cancer, these networks go awry in various ways, arming the cancer with the ability to abnormally grow, metastasize and evade drugs. Treatment that is based on understanding which components go wrong, and also how these go wrong in each individual patient, will improve cancer therapeutics. Dr. Pe’er will use genomic technologies to track how tumors respond to potent drug inhibition of critical pathways. She will develop cutting-edge computational machine learning algorithms to piece these data together and illuminate how a cell's regulatory network processes signals, and how this signal processing goes awry in cancer. By utilizing a large panel of diverse tumors in this study, she will begin to piece together general principles and patterns in drug responses.
These studies should show what drives cancers and what part of the networks should be targeted for treatment. For each individual patient, she will determine the best drug regime, informed by a model that can predict how the tumor will respond to drugs and drug combinations.
“We have the tools to do what we couldn't do before. Tools that we couldn't have even thought or dreamt of having to really study cancer, understand cancer, and figure out what can kill it. I think we’re in the most incredible, and hopeful time for cancer research.”
Identification and Targeting of Novel Rearrangements in High-Risk ALL
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and the leading cause of nontraumatic death in children and young adults. Until recently, the reasons why some people respond poorly to treatment have not been understood. Dr. Mullighan’s recent preliminary studies have used new genetic techniques to analyze leukemic cells obtained from children with ALL at high risk of relapse. This has identified new genetic changes that are associated with treatment failure, including alterations of the gene IKZF1, and previously unidentified chromosomal changes that activate genes that drive the proliferation of leukemic cells. These altered genes include ABL1, CRLF2, JAK2, and PDGFRB. These genes may be targeted by specific drugs, suggesting that patients with these alterations may be treated with these agents.
This project will determine the nature and frequency of these novel genetic alterations in ALL in children and young adults, and will use cutting-edge genomic profiling approaches to identify new genetic alterations in high-risk ALL. Dr. Mullighan will go on to develop experimental models that mimic human ALL in order to determine how these changes cause leukemia, in order to enable testing of new targeted therapies.
“There's enormous intellectual satisfaction about taking a problem that we don't understand and trying to create new knowledge.”
Exome Sequencing of Melanomas with Acquired Resistance to BRAF Inhibitors
Cutaneous melanoma ranks among the fastest rising human malignancies in annual incidence and is highly lethal when detected at advanced stages. Standard chemotherapy often targets fast dividing cells, in both the tumor as well as some normal tissues of the patient, giving rise to unwanted side effects. Targeting a specific feature of cancer not present in the normal cells would reduce undesirable side effects.
A small molecule (PLX4032) targeting a common melanoma mutation, V600EB-RAF, is showing unprecedented promise in advanced stages of clinical trials (80 percent of patients respond if their tumors harbor the V600EB-RAF mutation) but drug resistance occurs over time and leads to clinical relapse. Dr. Lo reported in Nature the discovery of two means by which melanomas escape from PLX4032, which suggest new treatment strategies that are testable in clinical trials. Discovering mechanisms of acquired PLX4032 resistance is logically the first step in constructing a therapeutic strategy closer to a cure.
Dr. Lo will study tissues derived from clinical trial patients. He will enlarge this tissue collection by collaborating among distinct clinical trial sites. Finally, because finding a specific mechanism among the myriad of cancer-related changes is akin to finding a needle in a haystack, he should capitalize on the latest, “high-throughput” genomic technologies. By harnessing the speed of “next-generation” DNA sequencing technology, he will examine the protein-coding regions of the melanoma genomes for key genetic alterations that account for acquired resistance. This effort will inform clinical trials and will help guide patient care.
“In cancer research today we’re experiencing accelerated discovery, so now is the time to use the most powerful scientific tools and to recruit the greatest talents. Our research is out of the box in the sense that we’re applying the latest technology to a problem that’s never been examined this way before.”
Chimeric RNAs Generated by Trans-Splicing and their Implications in Cancer
Genetic information flows from DNA to messenger RNA, and then to protein. In cancer, one of the hallmarks is DNA rearrangement, which results in the fusion of two separate genes. These gene fusion products often play critical roles in cancer development.
Traditionally, they are thought to be the sole product of DNA rearrangement, but Dr. Li recently discovered another mechanism that could generate the same fusion product without DNA rearrangement. This process is called “RNA transfusion RNA, which then is translated into a fusion protein. Dr. Li’s goal is to understand the physiological functions of the RNA trans-splicing process and its implications in cancer. He will identify examples of trans-spliced RNAs in normal and cancer cells, and validate the candidates identified through these approaches. Stem cell differentiation could shed light on the cells of origin for some mysterious cancers.
Because of the broadness of gene fusions in cancer, Dr. Li’s discovery has already raised concerns for false positive cancer diagnoses with current diagnostic methods, as well as for potential side effects in normal tissues caused by therapies targeting these fusion protein products. Dr. Li hopes to better characterize the trans-splicing process, and translate this knowledge into better diagnostic and therapeutic approaches.
“It is a promising time in cancer research because of the advances in technology, the information explosion, and new concepts being developed in cancer research. I think the puzzle pieces are there. We just need to put them together.”
Targeting PP2A and the Glutamine-Sensing Pathway as Cancer Treatment
Normal body cells grow, divide and die in an orderly fashion. Cancer arises if cells in a particular tissue begin to grow out of control. Most fast-growing cancer cells acquire mutations enabling them to take in more nutrients from the environment in order to divide. However, rapid tumor growth often leads to nutrient deprivation conditions in tumor cells. Cancer cells develop strategies to survive a low nutrient environment. Understanding these mechanisms is important for developing new drugs that could starve tumor cells to death and block cancer progression.
Glutamine and glucose are two major nutrients that support cancer cell growth and survival. This project will determine the molecular basis of tumor cell survival under glutamine deprivation in order to develop novel drugs targeting this pathway. To date, drugs designed to inhibit cancer cells from using nutrients have been successful in killing cancer cells. However, all these drugs have to be used at a high dose, resulting in toxic side effects. Thus, sensitizing cancer cells to these drugs by blocking cell survival mechanisms is necessary to inhibit tumor growth. Dr. Kong will test the idea that we can starve cancers to death by blocking the nutrient supply and PP2A, which is a phosphatase that plays a critical role in mediating cell survival upon glutamine deprivation.
If successful, this strategy is likely to be applicable to numerous tumor types, and therefore, this research will potentially benefit a large population of cancer patients.
“Stand Up To Cancer provides unique opportunities and lets us run instead of walk, because cancer patients cannot wait. I think everyone has his or her own responsibility to society. My responsibility is to cure cancer.”
Targeting Protein Quality Control for Cancer Therapy
The normal growth and proliferation of cells is orchestrated by a cascade of events that are initiated by the binding of a stimulus to a receptor at the membrane. Once triggered, the receptor communicates to the rest of the cell via recruitment of a number of signaling molecules. In cancer, the alteration of growth or survival signals can ultimately cause the signaling circuits to go out of control. Abnormal changes in receptor levels generate more cell changes that lead to uncontrolled growth. Most cancer therapy takes advantage of this phenomenon. Current drugs bind to these growth receptors at the membrane. However, drug resistance can develop over time.
Recently, Dr. Jacinto discovered that a protein complex, mTORC2, which is known for its function in activating the protein Akt, has a crucial role in protein production and quality control. Dr. Jacinto found that mTORC2 also controls growth receptors, such as epidermal growth factor receptor. Dr. Jacinto will examine this novel function of mTORC2 in regulating epidermal growth factor receptor expression and quality control. Inhibiting mTORC2 in cancer would prevent cell survival and blocking the expression of epidermal growth factor receptor before it reaches the cell membrane, thereby preventing growth of cancer cells. Dr. Jacinto will use cell and mouse models to inhibit mTORC2 in breast cancer cells.
This could have implications in a number of cancer types, and ultimately reveal new modes of therapy for breast cancer and other malignancies.
“The most inspiring thing for me is knowing that what we’re doing can help people.”
Targeting Genetic and Metabolic Networks in T-ALL
T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that requires treatment with intensified chemotherapy. Despite recent progress in the treatment of this disease, 25 percent of children and 40 percent of adults with T-ALL show primary resistant leukemia, or respond only transiently to chemotherapy and ultimately fail to be cured. Further treatment advances require the development of effective and highly specific molecularly targeted drugs.
This project will identify key genes that are essential for the proliferation and survival of T-ALL cells. To achieve this goal, Dr. Ferrando will use emerging technologies to compile a complete catalog of genetic alterations responsible for the pathogenesis of T-ALL to analyze how these mutations impact the circuitries that control normal cell growth, proliferation and survival. He will also analyze the effects of cancer mutations in the complex and intricate circuitries that control leukemia cell proliferation and survival. This T-ALL network represents a roadmap of how T-ALL mutations work, and how they interact with each other and will facilitate the identification of key genes and pathways. Selective inhibition of these genes will identify targets for the development of new, more active and highly specific anti-leukemic drugs.
This project represents a unique opportunity to exploit genomic technologies and develop new approaches to identify targeted therapies that will ultimately be applicable to a broad spectrum of cancers.
“We all appreciate that the boldest and most innovative projects are the ones that drive the field forward in a technological and conceptual way. The speed of development that we are seeing in science today is unprecedented. It’s very exciting.”
Targeting MLL in Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a form of cancer in which the normal development of blood cells is blocked and the cells multiply abnormally. AML affects children and adults, with about 12,000 new U.S. patients each year. A substantial portion of AML cases have extremely poor prognosis.
Although considerable progress has been made in understanding the causes of AML, the drugs currently used to treat AML are mostly cytotoxins and yield disappointing results with less than 20 percent of AML patients surviving after five years of treatment. The goal of Dr. Dou’s research is to identify a whole new class of drugs for AML that specifically target the tumor initiating cells. Dr. Dou believes this is very promising research that, to date, has not been pursued in a highly focused and coordinated way. Toward this goal, she plans to collaborate with other investigators with diverse expertise to develop compounds to target the enzyme that in humans is encoded by the mixed-lineage leukemia (MLL) gene. The goal of Dr. Dou’s proposed research is to further develop these and other drug candidates for AML so that they may move rapidly into clinical testing.
“You have to believe in what you are doing and you have to go through phases of frustration, knowing that one day if it's to prevail, it's going to be very good.”
Cancer Cell Specific, Self-Delivering Pro-Drugs
Tailoring a type of molecule that is naturally attracted to cancer cells with an anti-cancer payload, Dr. Levy aims to minimize the toxic collateral damage inflicted on healthy tissue and cells by conventional cancer treatment methods. The innovation of a precise, self-delivering agent would greatly diminish commonly harsh side effects, representing a leap forward for cancer patients in treatment.
“I fight cancer because I think we can find a cure. It’s a very complicated disease, but I think we can stop it.”
Modeling Ewing Tumor Initiation in Human Neural Crest Stem Cells
This project will use an innovative model to generate neural crest stem cells in the laboratory and will look at the ways in which expression of EWS-FLI1, an abnormal gene found in Ewing sarcomas, affects the epigenetic state in these neural crest stem cells and initiates tumor formation.
“We need to develop drugs that are going to selectively kill the cancer cell and spare the normal developing tissue. So that when the child has finished their treatment, they’re not only free of cancer, but they can go back to school and know that they’re going to live a normal, healthy life.”
An Emerging Tumor Suppressor Pathway to Human Cancer
The Hippo biochemical pathway is thought to regulate organ growth, bringing cell division to a halt once organs have reached maturation. One of the defining characteristics of cancer is rapid, unchecked cell growth. Dr. Fernando Camargo leads an IRG investigation into the promise of Hippo signaling and its possible role in suppressing cancer cell growth or providing model and material for new cancer therapies.
“Every once in a while you’re going to be the first person that notices something that nobody else in history of human kind has known, and I think that’s very exciting.”
Targeting Cellular Plasticity in Individual Basal-Type Breast Cancer Cells
Healthy cells lack the ability to survive outside their original niche, but during cancer progression, malignant cells acquire the ability to adapt to foreign environments. This property of adaptability, which is referred to as “plasticity”, is possible because tumor cells are able to re-configure their genetics to better fit the new niche they find when they spread to different organs. A similar adaptation process can occur when tumor cells are treated with drugs; although at first the drug may work against the tumor, internal processes in the cancer cells change to make them more resistant to therapy. The goal of this project is to better understand the fundamental internal processes of plasticity in cancer cells, so that we can find better ways to defeat metastases and drug-resistance.
While it is unclear how tumor cells perform the internal reconfigurations needed for adaptation, it is known that biochemical pathways that specialize in transmitting messages within the cell and controlling gene expression are involved. The Albeck lab has developed an imaging technique that allows these messaging pathways to be monitored continuously in living cells, providing a new window into how cells decide which genes to turn on or off. The hypothesis is that random periods of gene activity intensify as the cellular environment changes during tumor progression, allowing some tumor cells to activate genetic programs that provide them with a survival advantage. This hypothesis will be tested by combining the novel imaging technology with a cell culture system that mimics different points in a tumor’s progression. Cellular survival in response to chemotherapy will be tracked, as well as the random changes that provide cells with temporary resistance to drugs. By tracking the underlying diversity of evolving tumor cell populations and focusing on the most drug-resistant cells, the hope is to identify new treatment strategies that are more effective and have fewer side effects.
“You only have so much time in your life to make an impact, you might as well work on a problem and not just one that’s interesting, but one that’s actually going to help people.”
Uncovering How Rad51 Paralog Mutations Contribute to Cancer Predisposition
Changes in DNA, known as mutations, can arise during cancer and in some cases can also be a cause of cancer. Every day, our DNA is damaged from internal sources, such as free radicals, as well as external sources, such as ultraviolet light or radiation. Damaged DNA can lead to mutations and, in healthy cells, many proteins work together to repair DNA damage as it arises. One of the most toxic types of DNA damage a cell can encounter is called a DNA double-strand break (DSB) - even one unrepaired double-strand break will result in cell death. Cells have specialized proteins that work to fix DSBs. The repair process can stop working, however, if the DNA repair proteins are themselves mutated. Mutations in DNA repair pathways have been linked to a number of human cancers. This study focuses on a group of DSB repair proteins, known as the RAD51 paralogs, which have been linked to cancer susceptibility, particularly in breast and ovarian cancers. There are five RAD51 paralogs that work together to repair broken DNA and maintain the health of a cell. The goals of this project are to 1) understand the importance of the RAD51 paralogs in repairing DSBs; 2) understand why people who have mutations in any one of the RAD51 paralogs are more likely to develop cancer; and 3) determine novel methods for treating RAD51 paralog mutant cancers. The ultimate goal is to uncover individualized cancer treatments for these particular tumors to ensure that these patients will have the best outcomes.
“Whether it's a parent, a mother, a father, a brother, a sister, an aunt or uncle, we all have stories where we have been burdened by cancer.”
Phospholipid Messengers as Drivers of Dendritic Cell Dysfunction in Cancer
In 2016 it is estimated that more than 22,000 women will be diagnosed with ovarian cancer and over 14,000 will die from the disease. Novel and more effective therapeutic strategies are urgently needed in the clinic to improve the dismal prognosis of this devastating disease. A form of immunotherapy, adoptive T cell therapy, utilizes immune cells called T cells that are engineered in the laboratory to recognize and eliminate cancer cells. This type of immunotherapy has been used successfully in melanoma patients, however, there has only been partial success in ovarian cancer. This is thought to be because the ovarian tumor microenvironment, the cells and structures that surround and support the cancer cells, work to suppress T cell activity. Preliminary evidence from the Cubillos-Ruiz group has confirmed that dendritic cells, another type of immune cell that is common in the tumor environment, are programmed in such a way that they inhibit T cell function. This proposal aims to understand how dendritic cell signaling is altered in ovarian cancer tumors. Specifically, a novel immunosuppressive pathway driven by a unique class of molecules, called lipid messengers, will be characterized in the dendritic cells of the tumor environment. The hypothesis is that these lipids cause severe immune cell dysfunction which would limit the clinical benefit of adoptive cell therapy in ovarian cancer. Therefore, this proposal will also determine if blocking the activity of these immunoregulatory lipids could provide a new approach to improve the effectiveness of ovarian cancer immunotherapies.
“I lost my grandmother to cancer in 2012, and that was, of course, completely devastating for the family, but to me as a scientist, it was extremely frustrating to realize that what we call modern medicine couldn't do anything to stop the cancer.”
Metabolic Reprogramming Using Oncolytic Viruses to Improve Immunotherapy
The last several years have brought considerable progress to the field of immunotherapy, the goal of which is to stimulate and amplify a patient’s own immune response to recognize and destroy tumor cells. Despite the remarkable success of immunotherapy in some forms of cancer, many tumors do not respond because the cancer cells change their surrounding environment, termed the tumor microenvironment, so that it is restrictive to immune cell function. For example, tumor cells use molecules called immune “checkpoints” to suppress anti-cancer immune function. In addition, tumor cells need a lot of fuel to continue to grow, evolve and metastasize, and in so doing, effectively starve the microenvironment and incoming immune cells of the energy they need to carry out their anti-tumor functions. This proposal will focus on two immunotherapy approaches that have proven successful: 1) viruses that specifically infect and destroy tumor cells (oncolytic viruses) and 2) drugs that inhibit immune checkpoints thereby releasing the inhibition on immune cell function. The goal is to improve and combine the use of oncolytic viruses with immune checkpoint inhibitors to achieve a more potent immune response. First, cancer-specific viruses will be engineered so that they specifically target and destroy tumor cells and also reprogram the low nutrient immune suppressive conditions of the tumor microenvironment with the hope of enabling immune cells to function properly. Next, the oncolytic viruses will be combined with drugs that inhibit an immune checkpoint called PD-1 to see if the combination produces a magnified effect. These new, metabolism-targeting viruses, alone and in combination with checkpoint inhibitors, will be tested against melanoma in laboratory mice with the hope of bringing these new therapeutic approaches to patients in the future.
“As a young investigator, we are often told to do the ‘safe’ project to get yourself set up, and so [Stand Up To Cancer’s] funding flexibility [for] high risk, high reward projects is very attractive to make a monumental step forward rather than something that's incremental.”
“Weak Links” in Cancer Proteostasis Networks as New Therapeutic Targets
All cells must balance the amount of protein that they produce with the amount of protein that they discard. To achieve this balance, cells use robust systems to maintain protein homeostasis, a process that is termed proteostasis. Cancer cells are rapidly dividing and tend to accumulate genetic changes that result in mutated proteins. It is thought that this higher burden of mutated proteins makes cancer cells unusually dependent on the cellular systems that maintain proteostasis. Drugs that partially disrupt proteostasis have transformed patient care in some types of cancer, such as multiple myeloma. However, less than 1% of the factors within proteostasis pathways have been explored as possible targets for cancer therapeutics providing many possible opportunities to develop new cancer drugs targeted at these pathways. This study proposes to use cutting-edge genomics methods, coupled with dedicated drug discovery methods, to identify and validate the next generation of drug targets in the proteostasis network in multiple myeloma, castration-resistant prostate cancer, and aggressive forms of these diseases. Dr. Kampmann has pioneered a new genomics approach to rapidly identify the “weak points” in cancer cell proteostasis. The ultimate goal of this study is to create a genetic map of alterations in the dynamic proteostasis network, and to develop drugs that target those pathways as new cancer therapeutics.
“Yes, I have had cases of cancer in my family, and I think it has really brought home to me the urgency of what we do. We always want to think about our science as something that we want to translate as fast as possible to help people.”
Algorithmically-driven Quantitative Combination Cancer Therapy Engineering
Within a single tumor there are multiple, different cancer cell subtypes. This diversity means that the cancer cells can “try out” different ways to overcome the effects of anti-cancer drugs and to re-emerge as a more aggressive form of the disease. Thus, despite striking initial responses, the malignancy often evolves and adapts to the therapy, leading to recurrence. Combination therapies can block the ability of the cancer to evolve around any single therapy, but deciding on which drugs to combine, and how to combine them, is a major challenge. This project is focused on a new mathematical approach in designing combination therapy for chronic lymphocytic leukemia (CLL). In one approach, the investigators will genetically engineer CLL cells to recreate the diversity of cancer cell subtypes seen in tumors and will then determine which subpopulations are resistant to treatment with single agents or a combination of agents. In their second approach, the investigators will screen for genetic differences in CLL cells taken from patients before and during therapy to characterize how cells respond differently to drugs (administered to the patients or used in laboratory experiments). The measurements from these experiments will enable advanced mathematical models of leukemia growth, taking into account the fact that each population within the leukemia responds differently to different drugs. These data-driven models are expected to generate and optimize patient-specific combination treatment plans.
“The ability to help patients, with therapies, but also, just being there, supporting them, when they go through probably the hardest challenges of their lives, to me is immensely meaningful.”
Deubiquitinating Enzymes as Novel Anticancer Targets
A growing number of oncoproteins (proteins that promote tumor growth) and pro-metastatic proteins (proteins that promote the spread of tumor cells from the original tumor site/organ) have been extensively characterized. However, many of these cancer-promoting proteins have not themselves provided opportunities for development of new drugs. There is a need, therefore, for alternative therapeutic strategies directed toward cancer-promoting proteins. Much attention has been paid to a small protein called ubiquitin that is found in almost all tissues and serves as a tag that helps signal to cells how to regulate other proteins. Enzymes called deubiquitinating enzymes, or DUBs, remove ubiquitin from proteins thereby modifying function. The hypothesis in this research proposal is that DUBs substantially regulate key cancer proteins and pathways, thereby promoting tumor cell growth and metastases. Although DUBs have been considered as good candidates for drug development, no DUB inhibitors have entered the clinic. In humans there are 79 DUBs, providing a wealth of possible drug targets. This proposal aims to identify and target DUBs so as to inactivate some key oncoproteins or pro-metastatic proteins either by destabilizing these proteins or by changing their activity. Dr. Ma’s laboratory has already identified the first DUB that suppresses tumors by regulating the key anti-cancer protein, PTEN. In this study, Dr. Ma will screen a library of DUBs for those that regulate key oncoproteins and pro-metastatic proteins. In parallel, she will determine which DUBs promote tumorigenesis, metastasis, or therapy resistance. The identified cancer-promoting DUBs will be tested for the ability to serve as anti-cancer targets, paving the way for developing DUB inhibitors as new cancer drugs.
“I’m very heartened to see people fight for their life and help others. Their stories have motivated me to break through the barriers and find the cure for cancer.”
Imaging Cell-Level Heterogeneity in Solid Tumors for Personalized Treatment
Cancer is a complex disease that includes distinct groups of cells that are in the same tumor but react differently to treatment. This cell-to-cell diversity, or “tumor heterogeneity,” makes it difficult to eliminate all tumor cells because most drug combinations fail to kill a minority population of resistant tumor cells. These resistant tumor cells then grow and metastasize, resulting in recurrence of the disease in a more aggressive drug-resistant form. Pancreatic ductal adenocarcinoma (PDAC), which has a dismal 5-year survival rate of only 7%, is one of the most heterogeneous cancers, resulting in significant treatment resistance. Drug development for PDAC is significantly behind that of other cancers, with no effective targeted drugs on the market. Standard-of-care chemotherapies for PDAC exhibit varying degrees of toxicity and effectiveness and there is no rational system to match each patient with the least toxic and most effective drugs for their tumor. New approaches are needed to improve the care of cancer patients through new drug development, rational treatment planning, and reduced toxicities. The goal of this proposal is to address these gaps in drug development and treatment planning in PDAC, by directly measuring how different subtypes of cells within the same tumor respond to drugs. By extracting patient tumor samples and growing them in specialized conditions, tumor organoids (tumors in a dish) from individual cancer patients will be grown in the laboratory. Using a new imaging technology, individual cells will be assessed for drug responses while they are still growing side-by-side in a tumor organoid, mimicking what happens in a real tumor. The tumor organoid drug response data will be compared to real tumors taken from patients undergoing drug treatment before surgery so that this single-cell assessment technique can be validated as a way to measure heterogeneous drug responses in human PDAC. This novel approach to examine drug effects in heterogeneous tumors holds great promise for rational, personalized drug development and treatment planning.
“I have a responsibility to improve the state of [cancer] care because it’s hard to accept, so I refuse to accept it and work to make it better.”
Defining the Metabolic Dependencies of Tumors
Tumor cells require nutrients to survive and support tumor growth. These nutrients are provided by the cells that surround the tumor – the tumor microenvironment. Understanding the aspects of metabolism that are essential for tumor growth may reveal how best to exploit altered cancer metabolism and thereby identify targets for new drugs and improved cancer treatment. This proposal will study the fate of different nutrients within tumors in order to understand the aspects of metabolism that are essential for tumor growth. First, specially labeled nutrients will be traced within a tumor to understand the differences in nutrient metabolism in laboratory models of lung, pancreatic, and prostate cancers, compared to non-tumor models. Next, enzymes important for cellular metabolism will be genetically deleted from the laboratory models to determine which enzymes are critical for tumor initiation and maintenance. Lastly, existing therapies targeting metabolism will be selected to inhibit metabolic targets. The overall goal of this proposal is to define the metabolic dependencies of lung, pancreatic, and prostate cancer, to determine how best to use existing drugs targeting metabolism, and how to combine these drugs with new approaches to treat patients.
“I know what the realities are of how we treat cancer, and I have to say that touches me all the time, both from the standpoint of patients who I took care of ten years ago as a fellow who shouldn’t still be alive today, to people who we couldn’t make a difference for at the time.”
Defining the Mechanistic Connections Between Injury, Regeneration & Cancer
In mammals, there is a strong association of cancer with chronic damage to the skin, intestine, and liver. The connection is complicated, however, because the regenerative abilities of these organs serve to protect tissue integrity, reduce inflammation, and can instead resist cancer formation during injury. Dr. Zhu’s work focuses on a gene called Arid1a, which has been associated with cancer. Dr. Zhu has found that genetic deletion of Arid1a profoundly increases the healing capacity of the liver after injury without increased cancer. Indeed, deletion of this gene actually protects the laboratory mice against liver cancer. This proposal aims to understand the relationship between injury, regeneration, and cancer and more specifically to investigate Arid1a, and its related biological pathways, as new therapeutic targets in tissue repair and cancer. The hypothesis is that blocking regeneration suppressing genes like Arid1a will promote tissue regeneration and prevent or delay carcinogenesis. Using laboratory mice that are engineered to lack the Arid1a gene, Dr. Zhu’s lab will examine whether changing regenerative capability of injured livers and colons, influences cancer formation. They will investigate how a regenerating tissue influences nearby tumor cells in tissue. Lastly, they will perform a genetic screen in their laboratory mice to identify factors that influence Arid1a-associated tissue regeneration and determine how Arid1a may be connected with cancer.
“My mom had two cancers; a lot of what I do is always keeping patients like her in mind to try to do something that's going to change their outcomes.”
Harnessing Dipeptidyl Peptidase Inhibition for Cancer Immunotherapy
Cancer immunotherapy, in which a patient’s own immune system is harnessed to destroy cancer cells, is a revolutionary new approach for combating cancer. However, many cancers are not yet amenable to immunotherapy. Even for cancers for which immunotherapies exist, only a fraction of patients respond to such treatments. Additional research is therefore needed to identify new treatment options that target novel and/or complementary mechanisms of action. One particularly intriguing yet poorly understood small molecule drug, called Val-boroPro, has been shown to be an immune-stimulating agent with striking anti-cancer activity. However, significant toxicity concerns have so far impeded further clinical advancement. The mechanistic basis of Val-boroPro’s toxicity, and whether this toxicity can be separated from its promising anti-cancer efficacy, is not yet known. Dr. Bachovchin will address this question by determining the mechanisms of action of the drug to understand both why it is effective and why it is toxic so that only the anti-cancer mechanism can be exploited in future drug design. Using such drugs, this proposal aims to identify novel mechanisms to stimulate the patient’s immune system to eradicate cancer cells. This approach is unique in that it is distinct from the vast majority of ongoing studies that are focused on modifying or optimizing currently available immunotherapies. If successful, the proposed strategies could be rapidly translated into the clinic, where it will represent an entirely new mechanism for activating the immune system to kill cancer.
Rescuing T Cell Function for Immunotherapy of Pediatric Malignancies
CAR T cell therapy is very effective in pediatric leukemia and has yielded remission rates of more than 90 percent for children with relapsed acute lymphoblastic leukemia (ALL) in early stage clinical trials. However, there remain a significant number of patients eligible for this treatment for whom a CAR T product cannot be made. Dr. Barrett, through his experience with the pediatric CAR T cell program at Children’s Hospital of Philadelphia, has discovered that the main reason for this is the poor function of T cells from the patient—they are either defective or dead. Initial studies in the Barrett lab have shown that T cells from these patients have altered metabolic states. These metabolic alterations can be induced by chemotherapy but may also exist as part of the influence of particular types of cancer. Dr. Barrett seeks to identify the specific nature of these metabolic alterations in order to devise ways to reverse them, hence eventually enabling effective CAR T cells to be made. Additionally, the effect of chemotherapy on the metabolic status of T cells will be investigated in order to define therapeutic interventions to maintain T cell efficacy for immunotherapy in the face of chemotherapy. This innovative approach to understanding how to enhance CAR T-cell production should shed urgently needed light on the process of CAR T-cell generation.
Targeting the Pro-metastatic Niche in the Liver for Cancer Immunotherapy
Metastasis to the liver is a major cause of morbidity and mortality associated with a wide range of cancers, including gastrointestinal (GI) malignancies such as pancreatic ductal adenocarcinoma (PDAC). Immunotherapy, whose aim is to harness the body’s own immune system to fight cancer, has recently demonstrated considerable efficacy for patients with a variety of types of cancer, including patients with metastatic disease. However, outcomes vary tremendously among different patients and often do not last very long. In gastrointestinal malignancies, for instance, metastasis to the liver is common and associated with poor responsiveness to immunotherapy. In pancreatic cancer, which is predicted to become the second leading cause of cancer-related deaths by 2030, the liver is directly exposed via the portal vein to soluble factors and antigens released by developing tumors. Preliminary work from the Beatty lab has found that the immune microenvironment in the liver is conditioned early during pancreatic cancer development. This results in a liver that displays enhanced susceptibility to metastasis. Based on these findings, Dr. Beatty has developed the hypothesis that the immune microenvironment in the liver is inherently malleable; it has the capacity to support or suppress anti-tumor immunity. During cancer development, the microenvironment is induced to favor cancer cell metastasis and limit the efficacy of cancer immunotherapy. With this grant, Dr. Beatty will test this idea, and try to better understand the exact mechanism by which the liver may regulate efficacy to immunotherapy. By delineating the underlying mechanisms that generate a “pro-metastatic,” immunotherapy–resistant immune microenvironment within the liver, this work has the potential to provide novel opportunities for clinical intervention and to impact the lives of many patients.
T Cell Immunotherapy for Core Binding Factor Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a frequently fatal blood cancer with a number of different subtypes, many of which have characteristic abnormalities in certain genes and proteins. “Core Binding Factor (CBF)” AML is a type of AML that is named after the gene rearrangements that are characteristic of the subtype. CBF AML is relatively common in younger patients and although it has a better prognosis than some other types of AML, incomplete response to chemotherapy and/or relapse still often occurs, resulting in the death of many patients. The past few years have seen the development of several new and exciting types immunotherapy, including infusions of a category of immune cells called T cells that can be engineered to recognize and kill cancer cells. Unfortunately, most of the T cell immunotherapies available today are not suitable for AML because the proteins on the surface of cancerous AML cells are similar to the proteins on the surface of normal blood and bone marrow cells, leading to severe side effects when T cell immunotherapy also targets these normal cells. To address this issue, Dr. Bleakley aims to develop immunotherapy that targets abnormal cancer-specific proteins inside the cell rather than less-specific proteins on the cell surface. This strategy is based on her laboratory’s recent findings that certain parts of the abnormal proteins made in CBF AML can be recognized by T cells of normal, healthy people. The ultimate goal of this study is to harness the discoveries from this project to develop innovative T cell immunotherapies and therapeutic vaccine candidates for preclinical and, ultimately, clinical testing.
Imaging CAR T Cells with a Dual Function PET Reporter Gene
Immunotherapy has brought a sea change to how cancers are treated, with the potential for complete recovery from cancers with otherwise low survival rates. Among those therapies, CAR T cell therapy has shown dramatic activity in several hematological cancers, including advanced, chemotherapy-resistant acute lymphoblastic leukemia. In CAR T cells, a type of white blood cell called T cells that scan the bloodstream for cellular abnormalities and infections have been engineered with chimeric antigen receptors (CARs) that target tumor-associated antigens. These CAR T cells have shown activity in a number of hematological cancers, however a major obstacle in the development of CAR T cells that target solid tumors is the difficulty in determining the treatment efficacy and related toxicity because the fate of the therapeutically administered cells cannot be assessed directly. To address these issues, in vivo cell-tracking methods are critically needed to monitor noninvasively the fate of the administered cells in the body. To achieve this goal, Dr. Farwell proposes to develop a novel traceable genetic system that carries a potent “suicide gene.” With such a system, the fate of T cells will be monitored via a radiotracer using positron emission tomography (PET). Furthermore, the suicide gene function can be activated if the engineered T cells need to be destroyed because of undesirable and/or toxic effects. By developing such a tool, Dr. Farwell and his team have the potential to create a platform that opens the door to numerous imaging applications that will find widespread use in CAR T cell therapy and other cell-based therapies.
Identifying and Targeting Mechanisms of Resistance to Immunotherapy
A form of immunotherapy called immune checkpoint blockade therapy has revolutionized the treatment of metastatic melanoma. However, not all patients respond to this kind of therapy, and some who respond initially will later have progression in their disease. Understanding the mechanism of these varied responses could improve patient care for two reasons. First, patients who are more likely to respond favorably to the treatment could be identified before embarking on a treatment. Second, novel drug targets could be identified that have the potential to overcome resistance to the therapy. By analyzing samples from melanoma patients treated with immunotherapies, Dr. Haq and his team uncovered mutations in genes associated with treatment outcome. In some non-responding patients, mutations that hindered the ability of the patient’s immune system to destroy tumor cells led to treatment resistance. In other cases, mutations in genes without known function were identified that predicted beneficial response to immunotherapies. To understand better the role of genes associated with resistance or response to immunotherapy, Dr. Haq will use a unique tool developed in his lab to recreate resistance mutations in a mouse model. This platform will also be used to evaluate whether a drug currently in clinical trials can overcome immunotherapy resistance. Altogether, this approach could transform the way we understand and treat resistance to immunotherapy.
Reworking Negative Receptor Signals for Improved Anti-glioma T-cell Therapy
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor. Currently, the outlook for patients with GBM is poor: the five-year survival rate is less than 5 percent. Effective new therapies are urgently needed. Dr. Hegde and her team have utilized recent advances in cancer immunotherapy to generate chimeric antigen receptor (CAR) T-cells that specifically recognize the human epidermal growth factor receptor 2 (HER2), a protein that is specifically associated with GBM. A phase I trial conducted by Dr. Hegde showed that HER2-CAR T cells presented no treatment-related toxicities, and offered clinical benefit to 50 percent of the patients treated. Thus, while HER2-CAR T cells have high therapeutic potential, there is a clear need to improve their anti-GBM activity. In this project, a sophisticated methodology developed by Dr. Hegde and her lab will enable the development of T-cells able to kill GBM cells expressing HER2, and overcome/reverse the immune-inhibition of the tumor, with minimal toxicity. This study bears the potential to dramatically improve outcomes for GBM patients, and advance information leading to future standards in brain tumor immunotherapy.
Potentiating Novel Engineered Cellular Therapies for Solid Tumors
Glioblastoma multiforme (GBM), the most common malignant brain tumor, has a dismal prognosis, with median survival of only 12 to 15 months. Development of novel and targeted therapies are therefore critical to treat this devastating disease. Recent studies have raised hopes that immunotherapy, whose aim is to harness the body’s own immune system to fight cancer, and has recently established itself as a proven therapy for primarily leukemia and lymphomas, may be able to reverse this trend. In a recent clinical trial lead by Dr. Maus and her lab, one form of immunotherapy called Chimeric Antigen Receptor (CAR)-T cell treatment, was indeed successfully used to target cells containing a specific mutation present in 20-30% of patients with GBM. These engineered T-cells successfully trafficked to the brain and eliminated tumor cells with minimal toxicity. Based on this very promising preliminary work, Dr. Maus and her lab are now proposing to develop a second generation of CAR-T cells that target cancer cells with the specific mutation, and also modulate the immunosuppressive tumor microenvironment to maximize the efficacy of treatment in mouse animal models. The ultimate goal of this study is to engineer powerful T cells, resulting in a new form of potentially curative treatment for brain tumors. Furthermore, in addition to treating brain tumors, this technology has the potential to be applied as a therapy for other forms of cancer.
Delineating the Role of the Microbiome in Modulating Tumor and Host Immunity
In recent years, tremendous progress has been made in the treatment of melanoma and other cancers using immunotherapy, affording robust treatment choices for patients previously thought to have “untreatable” disease. However, a significant proportion of patients do not respond to these treatments, and there is a critical need to identify new strategies to enhance therapeutic responses. An area of study that warrants further exploration is the microbiome, the many different types of bacteria present in the human gut. There is now mounting evidence that the diversity of bacteria within the gut may affect responses to immunotherapy. In preliminary studies, Dr. Wargo and her team demonstrated that there was a direct correlation between the type of bacteria in the gut of patients with metastatic melanoma and their ability to respond to immunotherapy. Further, these differences were associated with differences in the population of immune cells in the patient’s tumors. To gain a better understanding of the mechanisms by which the gut microbiome may modulate immune responses to a range of immunotherapy, this project will explore the differences in the microbiome of patients that do and do not respond to such treatment, and devise strategies to change the microbiome to enhance the patient’s responsiveness to treatment. It is anticipated that results from these studies have the potential to lead to clinical trials incorporating strategies to enhance responses to immunotherapy (via modulation of the microbiome) for melanoma patients. It is also possible that those studies could be extended to other tumor types.
Reprogramming Tumor Immunogenicity with STING-Activating Nanoparticles
Cancer immunotherapy seeks to harness a patient’s own immune system to specifically destroy cancer cells throughout the body with minimal toxicity to surrounding tissue, while also training the immune system to “remember” how to kill cancer cells if they return. Recently approved checkpoint inhibitors have transformed the treatment of an increasing number of different types of cancer by reactivating T cells that recognize cancer cells. However, many patients still do not completely respond to this type of treatment. There are two primary and intertwined reasons for this: 1) patients have nonimmunogenic or “cold” tumors that are able to evade recognition by T cells, and 2) patients lack a sufficient number of the correct type of anti-tumor T cells necessary to efficiently destroy tumors. The aim of this research is to develop a safe and effective approach for increasing anti-tumor T cell responses within tumors and, by doing so, improve the effectiveness of checkpoint blockade immunotherapy. To achieve this goal, Dr. Wilson plans to develop “smart” nanoparticles coated with a small molecule that will act on the inflammatory pathway to turn “cold” tumors into “hot” ones, becoming recognizable by the immune system. Another complementary aspect of this project is to coat the nanoparticles with tumor antigens as well to better train T cells to recognize and attack cancer cells. Overall, this innovative proposal combines multiple approaches, using state-of-the art bioengineering, mouse tumor models, and a series of advanced proteomics and cell biology tools, and offers the potential to positively impact patient outcomes by developing a versatile, safe, and scalable drug-delivery platform for personalized immunotherapy.
Meet the Recipients
- Reprogramming Tumor Immunogenicity with STING-Activating Nanoparticles
- Delineating the Role of the Microbiome in Modulating Tumor and Host Immunity
- Potentiating Novel Engineered Cellular Therapies for Solid Tumors
- Reworking Negative Receptor Signals for Improved Anti-glioma T-cell Therapy
- Identifying and Targeting Mechanisms of Resistance to Immunotherapy
- Imaging CAR T Cells with a Dual Function PET Reporter Gene
- T Cell Immunotherapy for Core Binding Factor Acute Myeloid Leukemia
- Targeting the Pro-metastatic Niche in the Liver for Cancer Immunotherapy
- Rescuing T Cell Function for Immunotherapy of Pediatric Malignancies
- Harnessing Dipeptidyl Peptidase Inhibition for Cancer Immunotherapy
- Defining the Mechanistic Connections Between Injury, Regeneration & Cancer
- Defining the Metabolic Dependencies of Tumors
- Imaging Cell-Level Heterogeneity in Solid Tumors for Personalized Treatment
- Deubiquitinating Enzymes as Novel Anticancer Targets
- Algorithmically-driven Quantitative Combination Cancer Therapy Engineering
- “Weak Links” in Cancer Proteostasis Networks as New Therapeutic Targets
- Metabolic Reprogramming Using Oncolytic Viruses to Improve Immunotherapy
- Phospholipid Messengers as Drivers of Dendritic Cell Dysfunction in Cancer
- Uncovering How Rad51 Paralog Mutations Contribute to Cancer Predisposition
- Targeting Cellular Plasticity in Individual Basal-Type Breast Cancer Cells
- An Emerging Tumor Suppressor Pathway to Human Cancer
- Modeling Ewing Tumor Initiation in Human Neural Crest Stem Cells
- Cancer Cell Specific, Self-Delivering Pro-Drugs
- Targeting MLL in Acute Myeloid Leukemia
- Targeting Genetic and Metabolic Networks in T-ALL
- Targeting Protein Quality Control for Cancer Therapy
- Targeting PP2A and the Glutamine-Sensing Pathway as Cancer Treatment
- Chimeric RNAs Generated by Trans-Splicing and their Implications in Cancer
- Exome Sequencing of Melanomas with Acquired Resistance to BRAF Inhibitors
- Identification and Targeting of Novel Rearrangements in High-Risk ALL
- A Systems Approach to Understanding Tumor Specific Drug Response
- Targeting Sleeping Cancer Cells
- Inhibiting Innate Resistance to Chemotherapy in Lung Cancer Stem Cells
- Developing New Therapeutic Strategies for Soft-tissue Sarcoma
- Framing Therapeutic Opportunities in Tumor-activated Gametogenic Programs
- Coupled Genetic and Functional Dissection of Chronic Lymphocytic Leukemia
- Targeting Inhibition of BCL6 for leukemia Stem Cell Eradication
- Identifying Solid Tumor Kinase Fusions via Exon Capture and 454 Sequencing
- Therapeutically Targeting the Epigenome in Aggressive Pediatric Cancers
- Endogenous Small Molecules that Regulate Signaling Pathways in Cancer Cells
- Genetic Approaches for Next Generation of Breast Cancer Tailored Programs
- Modulating Transcription Factor Abnormalities in Pediatric Cancer
- Noninvasive Molecular Profiling of Cancer via Tumor-Derived Microparticles
- A Transformative Technology to Capture and Drug New Cancer Targets
- Functional Oncogene Identification
- Probing EBV-LMP-1’s Transmembrane Activation Domain with Synthetic Peptide