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Pancreatic Cancer Dream Team Progress Update

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Pancreatic Cancer Dream Team Progress Update

Cutting off the Fuel Supply: A New Approach to the Treatment of Pancreatic Cancer

Funding: $18,000,000 + $4,000,000 supplement + $250,000 supplement

Leader: Craig B. Thompson, M.D., president and chief executive officer, Memorial Sloan-Kettering Cancer Center
Daniel D. Von Hoff, M.D., senior investigator and physician-in-chief, Translational Genomics Research Institute (TGen)

Fast Facts on Pancreatic Cancer:

  • As the fourth leading cause of cancer death in the United States, pancreatic cancer remains one of the most deadly forms of cancer.
  • About 70 percent of people diagnosed with pancreatic cancer die within one year of diagnosis.
  • The overall 5-year relative survival for pancreatic cancer for 2004-2010 was 6.7 percent. (SEER).

Fast Facts on Prevention Tips:

  • Tobacco use is the most important avoidable risk factor for pancreatic cancer, accounting for up to 30 percent of the cases.
  • Exercise lowers the risk of pancreatic cancer. Obese people and those who have limited physical activity are more likely to develop exocrine pancreatic cancer.
  • Individuals who consume 3 or more drinks of hard liquor a day are more likely to die of pancreatic cancer.

    Project Background

    The Dream Team’s Research Project

    Pancreatic cancer is the fourth leading cause of cancer death in the United States, and approximately 70 percent of patients die within the first year of diagnosis. Recent advancements have had little impact on survival, and a new approach is desperately needed.

    Scientists have suggested that it might be possible to “starve” cancer cells to death by depriving them of a specific nutrient that they require for survival. Recent studies have demonstrated that most cells acquire changes in genes (mutations) that cause them to become addicted to the nutrients that produce the energy they need to grow and survive. In most cancers, this nutrient is glucose. But in pancreatic cancer, it is glutamine.

    Glutamine is an amino acid that helps build muscle mass, and it is used by some cells for energy. When a tumor uses excess amounts of glutamine, it can rob other cells of this important nutrient. This can lead to extreme weight loss, a condition common among pancreatic cancer patients. Furthermore, the waste that is produced when tumor cells use glutamine for energy causes normal cells to secrete growth factors that help the tumor cells grow. Cancers that use glutamine for energy also are often resistant to standard forms of chemotherapy, another characteristic of pancreatic cancer.

    The goal of this Dream Team is to develop tests that use advanced imaging techniques to determine which nutrients pancreatic cancer cells require to fuel their growth and survival. This information will allow scientists to develop more individualized treatments with fewer side effects. The Team is conducting a series of clinical trials to test therapies that can deprive pancreatic tumors of crucial nutrients. These therapies will be tested in combination with existing standard chemotherapy, with the goal of increasing patient survival beyond one year and improving quality of life.

    Status Update

    6 month milestones
    The Team initiated a multi-center, randomized phase III trial testing a two-drug combination on patients with pancreatic cancer.  Previously, a phase I/II trial showed that a combination of two therapies decreased a molecular marker of pancreatic cancer and increased patient survival in patients with advanced metastatic pancreatic cancer. The Team began enrolling patients with a goal to enroll 842 patients at 92 sites in the United States, Canada, Australia, and Russia.

    Team members at Princeton University and Johns Hopkins Medical Institutions created standard procedures for collecting, shipping, storing and analyzing samples. These tests were used for animal and xenograft tissues and are ready for use with human samples. A variety of methods to examine the cellular metabolism were validated, and next generation genome sequencing techniques will be used. Specific protocols were established to examine key genomic and metabolomic targets in pancreatic cancer samples collected from patients with advanced cancers. Collection and analysis methods have been standardized so that patient samples from across the country can be analyzed.

    Pancreatic cancers feed on glutamine, and understanding how they take in the nutrient and use it will open new avenues to combat the tumor. During this six months, significant progress was made in synthesizing forms of glutamine that can be tracked using advanced imaging techniques. One form was tested and efficiently taken up by the tumor in mouse models. Synthesis of another form of glutamine was optimized and ready for testing in mice.  This form is tracked using magnetic resonance instead of a PET/CT scan, allowing patients to avoid radiation exposure.

    12 month milestones
    The Team launched a phase I/II clinical trial of a three-drug combination therapy for patients with advanced pancreatic cancer.  This trial will combine the paired chemotherapy agents being studied in the phase III trial with a third drug that works by inhibiting a pathway called Hedgehog that is known to play a critical role in cancer growth. The Team also completed nuclear receptor profiling on two pancreatic stellate (support cells in the pancreas) cell lines. Comparisons of the two profiles will soon begin. The current leading candidate is the vitamin D receptor.
    In addition, the Team initiated a preclinical study investigating the efficacy of three agents that affect glucose and glutamine metabolizing enzymes. Fifteen individual patient tumors were implanted in mice, and treated with the above agents. Preliminary results indicate that Phenformin , which regulates glucose and lipid metabolism, is promising for pancreatic cancer therapy.

    18 month milestones
    The Team completed profiling analyses and comparisons of pancreatic stellate cells and normal pancreatic epithelial cells. The goal is to use this information to identify potential druggable targets, including androgen, glucocorticoid, and estrogen receptors. Drugs that are used to treat other types of cancer are already available for these targets.
    The Team also started studying potential glutamine imaging agents that may be used during the PET scans performed on cancer patients to monitor tumor growth. After regulatory approval is obtained, the first human studies will begin.

    The Team completed preclinical evaluation of four different targeted therapies: AOA, FX11, phenformin, and hydroxychloroquine. AOA is a glutamine metabolism inhibitor; FX11 is a glucose metabolism inhibitor; phenformin modulates glucose and lipid metabolism; hydroxychloroquine is an autophagy (controlled breakdown of damaged organelles in a cell) inhibitor. These findings led the Team to modify its phase I/II trial and use hydroxychloroquine instead of phenformin. They also started a phase II trial that is acquiring samples of tumor and normal tissue for biological endpoints in pancreatic cancer.

    24 month milestones
    By the 24-month mark, the Team had enrolled 719 of the targeted 842 patients in its double-blind phase III clinical trial to test a two-drug combination treatment in patients with advanced pancreatic cancer. In addition, they were treating 43 patients in their phase II clinical trial of a three-drug combination therapy for patients with advanced pancreatic cancer. This information will be used to identify potential druggable targets on the cancer cells.

    30 month milestones
    The Team has fully enrolled the 842 patients for its double blind phase III clinical trial and data analysis has begun. The phase II clinical trial of a three-drug combination therapy for patients with advanced pancreatic cancer has continued and, after 6 months follow up, the Team observes a partial response in 33% of the patients and stable disease in another 48% of the patients. 

    Enrollment is nearly complete for the 75 person metabolomics (the chemical fingerprints of all the cellular processes that take place in a cell) profiling study. The results from the first 25 samples led to the hypothesis that these tumors acquire their nutrients through ingestion of the fluid and proteins surrounding the cells by a process called macropinocytosis. The ongoing trial of hydroxychloroquine which blocks breakdown of nutrients from this process will test this hypothesis.

    The Team continues efforts to move the new glutamine tracers into a clinical trial at Memorial Sloan Kettering Cancer Center (MSKCC) and the University of Pennsylvania (UPenn). Clinical protocols, patient consent forms, and other documents were assembled for review and are still in process at MSKCC and UPenn. Additional PET imaging studies for evaluation of metabolic mechanisms of these new tracers were performed in other rodent models.

    36 month milestones
    The Dream Team has continued to make progress in its five clinical trials, of which three are closed to enrollment:

    • The phase III study of ABI-007(nab- paclitaxel) plus gemcitabine versus gemcitabine in advanced adenocarcinoma of the pancreas met its accrual target. Patients who received the combination therapy demonstrated a significant improvement in overall survival compared to patients receiving gemcitabine alone.
    • The phase II study of therapy selected by molecular profiling in patients with previously treated advanced pancreatic cancer met its accrual target and its primary endpoint of one-year overall survival for 20 percent of patients.
    • The phase I/II trial of gemcitabine + nab-paclitaxel + GDC-0449 (the Hedgehog pathway inhibitor) has been closed to enrollment based on interim analysis that it did not meet its primary objective.
    • The trial to investigate tumor and normal tissue for biologic endpoints in pancreatic cancer has nearly met its accrual target.
    • The phase II/pharmacodynamics study of hydroxychloroquine in combination with gemcitabine and nab-paclitaxel to inhibit autophagy in pancreatic cancer continues to enroll patients.

    Preclinical development of a combination therapy targeting multiple components of the mTOR signaling pathway supports the initiation of Highly Active Anti-Tumor Therapy (HAATT) in patients with pancreatic cancer. The trial for collection of pancreatic tumor samples has led to the observations that there may be genetic subtypes of tumors that correlate with patient outcomes, and tumors with Ras mutations including pancreatic cancer acquire nutrients through macropinocytosis. Additionally, the Team has shown that, in pancreatic tumor stellate cells, Vitamin D receptor (VDR) activation is potentially a new therapeutic approach in the treatment of pancreatic cancer.

    42 month milestones
    In the past six months, the Dream Team has continued to focus on its clinical trials and significant progress has been made:

    • The phase III study of ABI-007(nab-paclitaxel) plus gemcitabine versus gemcitabine in advanced adenocarcinoma of the pancreas met its primary endpoint of significantly improving overall survival. The median overall survival was 8.5 months for patients receiving nab-paclitaxel and gemcitabine versus 6.7 months for patients receiving gemcitabine alone. The results were reported at ASCO 2013 Gastrointestinal Cancer Symposium in late January 2013.
    • The data from the phase II study of therapy selected by molecular profiling in patients with previously treated advanced pancreatic cancer continue to be analyzed.
    • Upon re-evaluation of the stop criteria, following results of the phase III trial of nab-paclitaxel plus gemcitabine, the phase II study of gemcitabine and nab-paclitaxel in combination with GDC- 0449 (the Hedgehog pathway inhibitor) has been re-opened with an additional three patients enrolled.
    • The trial to investigate tumor and normal tissue for biologic endpoints has continued to enroll patients with tissue samples continuing to be analyzed.
    • A maximal dose of hydroxychloroquine was determined for the phase II study of hydroxychloroquine in combination with gemcitabine and nab-paclitaxel to inhibit autophagy in pancreatic cancer. The phase II part of the study is now open, with six patients enrolled.
    • The proper form of calcipotriol has been identified in the calcipotriol proof-of-concept trial in patients undergoing surgery for pancreatic ductal adenocarcinoma. The Dream Team is working with the pharmaceutical company to obtain access to the drug. High-throughput assays are being developed to evaluate cell signaling in tumor samples obtained from the trial.
    • The Dream Team has enrolled six patients in the phase 0 trial to test glutamine tracers in patients with localized and resectable PDAC with a goal of 20 patients. Early results indicate that glutamine imaging agents may be superior to glucose agents in visualizing brain metastases.
    • A protocol has been written and is waiting for institutional review board (IRB) approval for the trial involving biopsy before and after nab-paclitaxel and gemcitabine treatment followed by extensive metabolic/lipidomics and micropinocytosis studies. In addition, an assay to determine expression levels of micropinocytosis-associated genes has been developed by the Dream Team.
    • A protocol was proposed to Celgene who agreed to supply the TORC 1/2 inhibitor CC-223 for a trial of metformin plus rapamycin plus TORC1/2 in patients in which best response to previous treatment was achieved. Assays to evaluate the mTOR pathway are being developed, and the Dream Team plans to finish the clinical trial protocol and submit for approval in the next six months.

    48 month milestones

    • The combination of nab-paclitaxel (Abraxane) plus gemcitabine, reported by this Dream Team to significantly improve overall survival in advanced pancreatic cancer by almost 2 months, is now FDA approved as a first-line treatment of patients with metastatic adenocarcinoma of the pancreas.
    • A new study will collect tumor samples from patients before and after treatment with nab- paclitaxel plus gemcitabine to determine the mechanism for the combination’s beneficial effects.
    • The team continues to recruit patients to two clinical trials that add a third drug to the nab- paclitaxel/gemcitabine combination. The trials will test if addition of either Vismodegib (GDC- 0449, a hedgehog inhibitor), which is approved for treatment of basal cell carcinoma and medulloblastoma, or the anti-malarial hydrochloroquine (an autophagy inhibitor), can improve further on the benefits of the nab-paclitaxel/gemcitabine combination.
    • This Dream Team has developed a better dye (18F fluoroglutamine) for imaging pancreatic tumors by positron emission tomography (PET). Compared to the standard technique (18F fluoro-D-glucose PET), the new dye appears better for identifying pancreatic tumors that have spread to the brain and liver. Additional testing is planned starting in January 2014 to confirm their findings.
    • The team continues in-depth analysis of gene mutations and metabolic changes in patient tumor samples. These efforts aim to personalize treatments so that patients receive the best course of therapy for their disease, and to find new therapeutic targets in pancreatic cancer.

    54 month milestones

    • Trials from this Dream Team testing whether addition of a third drug will improve the front line therapy for pancreatic cancer, nab-paclitaxel/gemcitabine, are well underway and steadily recruiting patients. The drugs being tested are a basal cell carcinoma/medulloblastoma treatment (Vismodegib) or an anti-malarial agent (hydrochloroquine).
    • The Dream Team has started a new pilot trial to test whether a vitamin D-like compound can be used to reprogram the cells and structures that surround and support cancer cells in pancreatic tumors.
    • A new trial is exploring whether “maintenance” therapy can be used successfully in patients after they have completed chemotherapy. They are exploring an anti-growth drug called metformin with or without another anti-growth drug called rapamycin.
    • The team continues in-depth analysis of gene mutations and metabolic changes in patient tumor samples toward discovery of new drugs and to personalize treatments so that patients receive the best course of therapy for their disease.

    60-month milestones

    • In laboratory studies, this Dream Team has found that a vitamin D-like compound can reprogram the tumor microenvironment - the cells and structures that surround and support pancreatic cancer cells in tumors – so that anti-cancer drugs work better. They are now testing the addition of a vitamin D-like drug to chemotherapy in clinical trials.
    • The Dream Team is continuing development and testing of a new imaging method to scan patients for pancreatic tumors and metastases. The results are promising that this approach is safe and effective, and may be superior to current techniques for some cancers, including pancreatic cancer.
    • The Dream Team continues to enroll patients in their ongoing trials that test addition of Vismodegib (a basal cell carcinoma/medulloblastoma treatment) or hydrochloroquine (an anti- malarial agent) to the front line therapy for pancreatic cancer, nab-paclitaxel/gemcitabine.
    • The Dream Team’s new trial of two anti-growth drugs, metformin and rapamycin, as “maintenance” therapy after chemotherapy is enrolling patients and going well.

    66-month milestones

    In their final 6 months of SU2C funding the Dream Team continues to analyze recently completed studies and report continued progress and new findings as follows:

    • The Dream Team has had success in developing a new imaging method to scan patients for tumors. The new imaging approach, which measures glutamine in the tumors instead of the standard measurement of glucose, works well in a number of different cancer types, including pancreatic cancer and is better than glucose imaging in brain cancer.
    • Dream Team members are now testing if glutamine imaging can help identify tumors that will be most sensitive to particular drugs, which will help doctors to select the best treatment for some patients.
    • The Dream Team has performed genetic analysis of pancreatic cancers and found:
    • Genetic mutations in four genes that may predict better survival after surgical removal of pancreatic tumors;
    • A number of genetic mutations that are “clinically actionable”, meaning that there are existing drugs that could be used to treat the cancer. They found that 38 percent of pancreatic tumors had clinically actionable mutations.
    • The Dream Team showed that early detection of pancreatic cancer was possible by testing blood samples for tumor DNA, a “liquid biopsy”. They found that the blood test was a much more sensitive way to find out if disease had recurred - compared to standard-of-care imaging approaches; the return of the disease was identified 6.5 months earlier using liquid biopsy testing, compared with using imaging techniques.

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