Facilitate the transition of projects from the laboratory to the clinic. Translational researchers seek to apply basic knowledge of cancer and bring the benefits of the new basic-level understandings to patients more quickly and efficiently. These grants are $600,000, three-year commitments
Lung cancer is the leading cause of cancer death in the US and worldwide, and non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. A subset of these cancers has a “driver” gene mutation the epidermal growth factor receptor (EGFR) for which targeted agents are highly effective in causing tumors to shrink. However, it never cures patients and the tumor always grows back. This proposal focuses on why the cancer is not completely killed even though all of the tumor cells have this mutation, and how to overcome this problem and kill the cancer more thoroughly. Our published and preliminary data have demonstrated that targeted therapy rapidly induces drug persistent cancer stem cells (DPCs) within days of starting therapy, and these DPCs don’t die with the drug. We show that this therapy specifically activates other genes called Notch3 and β-catenin that are essential for this effect. We show in animal experiments that targeting both EGFR and β-catenin result in reduced numbers of DPCs, and improved depth and duration of response and overall survival. This is a completely different approach than trying to target drug “resistance” pathways that develop months after initiation of therapy due to the “persistence” of tumor in the early days of therapy. Our goal is to eliminate tumor persistence so that it doesn’t have the chance to develop resistance, resulting in the cure of these patients. In this application, we propose to study how this persistence happens and attempt to move toward curing these patients by targeting β-catenin in combination with EGFR in a pilot human clinical trial. Successful completion of the proposed research will increase our understanding of why tumor cells are not eradicated with EGFR targeted therapy and test a novel drug combination that we hope will improve the survival of these patients.
Funded in partnership with Adenoid Cystic Carcinoma Research Foundation (ACCRF)
We recently found that retinoic acid treatment reduces the growth of a salivary gland tumor. The retinoic acid has the ability to shut down the cause of the cancer which is due to the overactivity of a gene called c-myb. Retinoic Acid has been successfully given to patients with a rare type of leukemia and we plan to use the same doses as the leukemia patients. We will examine whether the retinoic acid is active in the tumor and whether the growth of the tumor is reduced. Our studies have the possibility of finding the first treatment for this metastatic tumor.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
People who have been treated for cancer are not only at risk of cancer returning, but also at risk of long term side effects of their treatments some of which may threaten their life, including heart disease and other cancers. Medical teams are always searching for new ways to identify and reduce these risks.Some people will develop changes in their blood cells called “Clonal Hematopoiesis”(CH) and people with these changes have recently been found to be at higher risk of developing serious problems such as cancer and heart attacks and dying. CH is found more in older than younger people and more commonly in people who have been treated for cancer. We don’t know how common CH is in cancer survivors, who is at risk, when it develops and when and if we should be looking for it. But we are finding it more commonly with genetic tests that are being done as a part of their care. Our team hopes to provide answers to these questions by looking for CH in a group of women who were treated for breast cancer at a young age and agreed to give us blood samples and let us follow them over time. We will do special testing to find CH in their stored blood and see how it is different in different women, and changes over time. We will also ask them how they might feel about learning about CH results if they had CH, how learning about these risks that might affect them, and what they might need to support them best to help them to manage these risks. We hope this research leads to findings that can be used to understand this problem better and to improve how we take care of cancer survivors both now and in the future.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Leukemias represent cancers of the blood and are caused by genetic changes (mutations) in our blood cell that drive uncontrolled cell growth. Cancer survivors are more likely to develop leukemia than the general population. Traditionally this was thought to be a consequence of toxicity from the treatments used to fight their cancer, which leads to the development of therapy-related myeloid neoplasm (tMN) one of the most deadly and challenging to treat cancers. However recent studies show that leukemia associated mutations can be found many years before cancer diagnosis and interestingly, these blood mutations can also be seen in healthy people who never develop leukemia. This is phenomenon is called clonal hematopoiesis (CH). Our group has shown that CH is frequent in cancer patients and we find that cancer treatment may promote growth of cells carrying such mutations. To understand the effects of cancer treatment in patients that carry such mutations and how this dictates subsequent progression to leukemia, we propose to study a total of 45,000 cancer patients at time of cancer diagnosis. This will identify individuals with CH at time of diagnosis. We will then follow up patients and study the effects of oncologic therapy to analyzed for the presence of CH and study the effects of distinct cancer treatments on CH. Our study will help us understand tMN and guide the development of interventions to prevent tMN.
Year one is partially funded by UNICO in memory of Toni Alongi
Survivors of childhood leukemia (ALL) who are treated with chemotherapy develop poor cognitive skills (e.g. attention, speed of thinking, reasoning). These poor cognitive skills cause problems with school, work and peer interactions. The survivors also display abnormalities on brain imaging. We demonstrated that fluid collected during a spinal tap (i.e. cerebrospinal fluid [CSF]) contained markers of brain injury. However, our initial study was too focused on specific brain cells. We could not identify the cause of the brain injury. Thus, we want to conduct another study to examine many more protein markers before and after chemotherapy treatment.
We will use an advanced process to identify over 4,000 proteins in the CSF. This will permit us to determine the cause of the brain injury. We will compare the proteins to sex and age of the survivors. We will also compare the proteins to the treatments the survivors got. Finally, we will compare the change in proteins to brain imaging and cognitive testing.
CSF samples from a recently completed trial have been collected and frozenat −80°C so they will not decay. The brain imaging and cognitive testing is currently being completed as part of an institutionally funded protocol. For the current project, we will process the CSF samples and link them to adverse events and clinical outcomes.
With this comprehensive approach, we will identify which survivors are at greatest risk, and identify targets to prevent brain injury in future clinical trials.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Aromatase inhibitors (AIs) are important drugs for treating breast cancer. These drugs lower estrogen levels and reduce the chance that a woman will die from cancer. However, about one in five patients stops taking the drug early because of aggravating muscle and joint pain. Stopping the drug too soon can increase her risk of her cancer coming back. We do not know why women develop this pain, but it might be due to very low estrogen levels. We also do not know how to prevent the pain. Oxylipins are fat particles in the body that can increase or decrease pain. We believe that when a woman is treated with medicine that lowers her estrogen levels, that leads to more fats that cause pain. By also taking omega-3 pills, we believe that women instead will have more fats that decrease pain. This will allow her to continue to take the AI medication. To address this question, women who are starting to take an AI will also take either omega-3 pills or olive oil pills. We will ask if they develop pain and also check the levels of fats in their blood. Through this study we will find out if omega-3 pills prevent this side effect, and will learn more about how the AI medicine causes the pain. Knowing more about why women get this bothersome pain and how to prevent it will allow doctors to better treat patients and will allow more women to continue taking this life saving medication.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Cancer survivors often continue to havecertain side effects of anti-cancer drugs long after treatment has ended. Their hands and feet may feel numb, or they may feelunpleasant sensations in their hands and feet like burning. The simple touch of clothing or holding a cold can of soda may feel painful. Pin prick or paper cuts may hurt more than expected. These abnormal sensations are called chemotherapy-induced peripheral neuropathies (CIPN). They can seriously diminish the quality of life, and interfere with self-care and activities of daily living. Sixty-eight percent of patients report these abnormal sensations when asked 30 days after the end of anti-cancer treatment.Although the abnormal feelings may decrease over time, they can persist for months to years in as many as 30% of cancer survivors. Advances in diagnosis and treatment of cancer have increased the number of survivors to nearly 14.5 million. Of these, up to 4.5 million may continue to suffer CIPN long after their treatment has ended. There are no effective drugs for these survivors. We recently discovered thatNIAGEN®, a type of vitamin B3 that increases levels of NAD+, can prevent abnormal sensations in a rat model of CIPN.Importantly, it can also reverse CIPN that persists after the last dose of paclitaxel. The goal of this study is to translate these laboratory findings to the clinic and the patient. Here, we will determine whether daily treatment with NIAGEN can relieveresidual persistent CIPN in cancer survivors.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
While immunotherapy can sometimes result in dramatic and prolonged responses, it can also cause major toxicities. Immune-related adverse events (irAEs) are quite different than the toxicities seen with other cancer treatments, such as conventional chemotherapy. They occur when immunotherapy causes the patient’s own immune system to attack normal organs in the body. These toxicities may occur at any point in treatment, may be severe, and—of particular concern to cancer survivors—may be permanent.
irAEs remain poorly understood partly because immunotherapy research has focused almost exclusively on tumor biology, which is certainly relevant to immunotherapy effectiveness.However, we believe that toxicities irAEshave more to do with patients’ own immune systems.Our researchteam has expertise in cancer, immunology, and genetics. We have already collected clinical information and blood samples on hundreds of patients receiving cancer immunotherapy. With this information, we have identified some blood-based tests that may predict the future development of irAEs.
We now take this research to the next level by proposing genetic and functionaltests to identify underlying predisposition to irAEs. Specifically, we will study DNA and RNA in blood samples from our existing patient cohort. If successful, our research could ultimately help (1) identify high-risk patients, (2) customize therapy, (3) tailor monitoring, (4) expand immunotherapy use, and (5) prevent toxicities.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Hematopoietic cell transplantation (HCT) can cure cancer in many patients, but some survivors will develop a devastating complication calledbronchiolitis obliterans syndrome (BOS). BOS causes debilitating scar tissue in the lungs. Patients with BOS can experience shortness of breath, lung infections and long-term breathing problems. Some patients will die from BOS. BOS is hard to treat because most patients are diagnosed with after permanent damage has been done. If we can diagnose BOS earlier, before patients have symptoms, we might be able to prevent suffering. HCT patientswho have a condition calledchronic graft-versus-host disease, in which donor cells attack the patient’s tissues,are more likely to develop BOS. Our study will enroll patients with chronic graft-versus-host disease and test whether a simple tool called a spirometer can detect the earliest signs of BOS. We will give study participants a handheldspirometertomeasure how well a participant’s lungs are functioning. During the study, participants will use the spirometerevery week at home.The spirometer connects to the participant’s smartphone. The results will be sent to the study team over internet. If the team sees that a participant’s lung function begins to decline, the participant’s doctor will be informed.We hope that this tool can help a patient’s doctor diagnose and treat BOS earlier. Our ultimate goal is to ensure that patients who survive cancer also thrive after their treatment.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Anthracycline chemotherapy is used to treat over 50% of childhood cancer, and has resulted in improving in survival, such that over 85% of children now survive 5 or more years after a cancer diagnosis. Unfortunately, heart failure is an unwanted side-effect of anthracyclines, and is one of the leading causes of death in children cured of their cancer. Childhood cancer survivors are at a 5-15-fold higher risk of serious heart problems compared to the general population. The risk of heart failure increases with anthracycline dose, but the risk differs from child to child. Several studies have looked at the cause of heart failure at the DNA level. However, it is important to take this investigation to the next level, that is, truly understand the basic causes of at heart failure caused by anthracyclines. We propose to do this in a large study across 141 childhood cancer hospitals, where we are collecting blood samples from 300 childhood cancer survivors who have developed heart failure and 300 childhood cancer survivors who did not develop heart failure. We will use this information to get a deeper look at how anthracyclines cause heart failure. We hope that this will help us identify patients at highest risk, providing guidance in developing new ways to prevent and treat this unfortunate complication.
