Standard treatment for advanced bladder cancer is platinum-based chemotherapy. Unfortunately, this kind of treatment fails in most patients, and in some, it causes life-threatening heart problems. Today, doctors have no way to figure out who would benefit from platinum-based chemotherapy. Our team of researchers from Memorial Sloan Kettering Cancer Center (MSK) thinks that there are genetic reasons why this kind of chemotherapy works for some patients and not others. Pharmacogenetics is the study of how someone’s genetic make-up influences the way they respond to a drug. The goal of our research is to conduct the most comprehensive pharmacogenetic study to date to identify genetic reasons why some patients respond to chemotherapy and some experience lethal heart problems. The generous funding from the V Foundation will allow us to study the DNA of 500 advanced bladder cancer patients from MSKCC who received platinum-based chemotherapy and were then monitored for treatment response and heart problems. We will use a new genetic tool called the OncoArray to measure over 500,000 common genetic differences in those who respond to chemotherapy and those who do not. In addition, we will perform genetic sequencing to investigate rare genetic differences that may be important. Our study has the potential to enable doctors to tailor treatment to the individual patient in order to deliver the best bladder cancer care possible.
In addition to breast cancer, women who carry a defective copy of the BRCA2 (Breast Cancer Susceptibility) gene live with an incredibly high risk for ovarian cancer. Alterations in the BRCA2 gene can be passed down from parent to child (hereditary mutation) or may arise spontaneously (somatic mutation) in ovarian tumors. The biological role of BRCA2 is to repair damage to the human genome. However, the specific details of how defects in BRCA2 lead to ovarian cancer remain to be defined. The foundation of our collaborative research effort is to elucidate the molecular and genetic wiring that underlie this lethal malignancy. By identifying key players and pathways that drive ovarian tumor growth and treatment resistance, we can expose vulnerabilities that will guide the development of targeted therapies, novel biomarkers, and improve outcomes for patients. One of the highlights of the past two decades of research into BRCA biology was the discovery that patients can be treated with PARP inhibitors, drugs that target a specific DNA repair pathway, resulting in dramatic killing of BRCA deficient tumors. Unfortunately, not all patients respond to PARP inhibitor therapy, and some patients eventually relapse, thus detailed knowledge of the molecular mechanisms that lead to tumor formation and treatment resistance are needed. Our goal in this team-based research effort is to understand how PARP inhibitors selectively target BRCA2 deficient ovarian tumors, identify the molecular routes to PARP inhibitor resistance, and leverage these findings to impact clinical decision rules.
Tumors that spread to the brain, called brain metastases, are the cause of death of half of patients with metastatic melanoma. The metabolic environment of the brain is uniquely low in two amino acids, serine and glycine, which carry messages between nerve cells. This ensures accurate nerve cell communication, but should prevent or slow the growth of tumors, as tumor cells need large amounts of serine and glycine to make DNA and proteins to divide and grow. Yet, tumors can spread to the brain, and are incurable once they have done so.
We hypothesize that tumors metabolically adapt to the brain’s metabolic environment by increasing their ability to make serine and its product glycine, and that blocking the production of serine should either attenuate the development of brain metastases or help treat existing brain metastases. We will determine if serine synthesis is increased in brain metastases, and if tumor cells adapt to, or are selected for, the environment of the brain by increasing their production of serine and glycine. In addition, we have developed small molecules that inhibit serine synthesis, and will test these compounds in mouse models of melanoma brain metastases with the goal of reducing their initiation or growth. These studies will demonstrate that targeting the serine synthesis pathway might be useful in treating melanoma brain metastases and offer proof of concept that small molecule inhibitors of serine synthesis might be effective in treating patients with melanoma brain metastases and brain metastases from other tumors.
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women. The primary cause of death is metastasis, or spread of the cancer via the blood stream to other organs, which is incurable and associated with an average life expectancy of only 3 years. Although breast cancer death rates have declined due to screening and more effective treatments, more accurately identifying metastatic risk in order to prevent overtreatment remains a major clinical challenge. Therefore, the most important problems in breast cancer include reducing overtreatment by identifying more accurate prognostic markers and preventing spread of cancer cells in those at risk. Our program has focused on addressing these problems by studying breast cancer cell dissemination at single cell resolution using innovative experimental methods, with a focus on translating these discoveries into the clinic through multidisciplinary collaboration. In aim 1, we will confirm the association of 2 specific breast cancer tests that may more accurately identify who is at risk for recurrence, one of which identifies microscopic structures (which we call “TMEM”) that seed tumor cells into the blood and other organs. In aim 2, we will test a new drug which blocks TMEM function to see if it can block seeding of tumor cells into the blood. The project is therefore studies an entirely new approach to cancer diagnostics and treatment. The basic science studies that led to this work have been described in an award winning video entitled “Spying on Breast Cancer Metastasis” (https://www.youtube.com/watch?v=q_JDp-VePAs)
Over the past decade, harnessing the power of a patient’s own immune system for the treatment of cancer has been a major medical breakthrough. By using drugs to block inhibitory signals on immune cells, these medicines help “release the brakes” allowing them to kill cancer cells. Given the tremendous success of this approach, our lab has worked to identify another class of drugs that help “wake up” the immune system to help it fight off cancer. We have performed extensive studies on a protein called CD40, which is naturally used by the immune system to fight off infections. By activating CD40, cells of the immune system are better able to recognize and kill cancer cells. We modified a class of drugs, called antibodies, to help stimulate CD40 on immune cells. By doing this, we generated a drug which was twenty-five times more potent than the currently available form. This enhancement led to better immune system activation and treatment of cancer. We are now aiming to test this improved immune therapy in patients with cancer, hoping to provide another class of drugs that help the immune system attack and kill cancer cells.
Pancreatic cancer remains a lethal illness with limited treatment options. While harnessing the immune system has demonstrated dramatic results in controlling other cancers, it has so far failed in pancreas cancer. The development of effective immunotherapy for pancreatic cancer requires the activation and expansion of immune cells that recognize and kill the cancer. We have developed a cancer vaccine by fusing malignant cells with powerful immune stimulating cells known as dendritic cells that are capable of inducing anti-tumor immunity. This strategy allows the immune system to see cancer antigens so that they can be recognized and attacked. This vaccine showed excellent results in clinical trials in patients with blood cancers. One challenge to developing a vaccine for pancreatic cancer involves obtaining adequate tumor tissue needed to create a personalize vaccine. We have solved this problem by developing a culture system that allows for growth of a patient’s tumor tissue in vitro known as organoids that can subsequently be fused with patient’s own dendritic cells created personalize vaccine. In our first aim, we will conduct a clinical trial in patients with pancreatic cancer to show the feasibility, safety, ability to stimulate a immune response and preliminary efficacy of the vaccine product. While we expect that this strategy will be feasible and work in some patients, it is likely that it will not be enough for all patients. For that reason, in the second aim, we will work with mouse models to combine the vaccine with strategies that could make it better.
Funded by 2012 The V Foundation Wine Celebration and Jimmy V Celebrity Golf Classic
The attacks on the World Trade Center (WTC) on Sept 11, 2001 created an environmental exposure to WTC aerosolized dust and gases that contained known and suspected carcinogens. We continue to prospectively follow the entire FDNY cohort of firefighters and emergency medical service (EMS) workers that were exposed to these carcinogens for cancer incidence and have proposed to conduct studies to estimate the prevalence of blood cancers (myeloma and myelodysplastic syndromes) and pre-cancerous conditions in a subset of this cohort. Studies being conducted at Dr Landgren’s lab at Sloan Kettering are analyzing the proteins in the blood samples for detection of myeloma and pre-myeloma disorders. Studies at Dr Verma’s lab are using genome sequencing technologies to detect for the presence of cancer associated mutations in these samples. Dr Prezant’s group at FDNY has built infrastructure for the collection of the samples and has led to successful banking of over 3000 samples from firefighters exposed to the WTC disaster. Data generated from these studies will uncover the effects of WTC exposure on the development of blood disorders and also demonstrate the role of environmental exposures on cancer in general.
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