Innovative Research Grants 2016
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.
IRG Recipients at a Glance
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.”
Meet the Innovative Research Grants 2016 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