Translational Archives - Page 15 of 31

Donna Hammond, Ph.D.

Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund

Cancer survivors often continue to have certain side effects of anti-cancer drugs long after treatment has ended. Their hands and feet may feel numb, or they may feel unpleasant 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 that NIAGEN®, 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 relieve residual persistent CIPN in cancer survivors.

David Gerber, M.D.

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 irAEs have more to do with patients’ own immune systems. Our research team 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 functional tests 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.

Guang-Shing Cheng, M.D.

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 called bronchiolitis 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 patients who have a condition called chronic 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 handheld spirometer to measure how well a participant’s lungs are functioning. During the study, participants will use the spirometer every 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.

Smita Bhatia, M.D., MPH

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.

Saro Armenian, DO, MPH

Funded by the Stuart Scott Memorial Cancer Research Fund

Stem cell transplantation is an effective way to treat patients with blood cancers. However, this treatment can cause short- and long-term side effects. These side effects may affect quality of life and increase risks for other diseases. Doctors must balance these risks with the potential for stem cell transplant to cure patients. A risk-prediction model can help with such decisions, but current models are inadequate. Risk-prediction models are often based on a patient’s age, but people of the same age in years may not be alike in terms of underlying health. Underlying health can be estimated with various “biomarkers.” Our proposal is designed to identify a new biomarker that shows whether a patient is fit for stem cell transplant. We are studying clonal hematopoiesis of indeterminate potential (CHIP), a group of genes that indicate the health of a patient’s blood cells. Our hypothesis is that patients with CHIP in the blood before stem cell transplant will have poor outcomes after transplant. To test this, we will use a large collection of blood samples taken from blood cancer patients before stem cell transplant. We also have information about each patient’s health after transplant. We will use DNA sequencing to measure CHIP genes in the blood samples. We will use statistics to compare CHIP in the samples with patient health after stem cell transplant. If these correlate, it will show that CHIP is a good biomarker for use in a risk-prediction model. This will help doctors make personalized decisions that improve the lives of blood cancer patients.

Jaime Modiano, Ph.D., D.V.M.

Funded by the Dick Vitale Gala

Sarcomas are cancers of bone and connective tissue. These cancers are not very common in people, but they are no less serious than other, more common cancers. One reason there are few new treatments for sarcoma is that their rarity makes it difficult to obtain material for study. To overcome this, we have studied sarcomas in animals, and especially in pet dogs. Dogs share our environment and their risk to develop cancer is about the same as it is for humans. But unlike people, dogs develop sarcomas very commonly. Over the past twenty years, we have found how sarcomas of dogs are like sarcomas of people. This creates opportunities to develop new sarcoma treatments in dog “patients”. For this project, we are studying how we can activate the immune system to kill sarcomas – and specifically bone cancer. Our strategy starts with a virus that infects and kills cancer cells. Because this allows the immune system to recognize the tumor, we can then add a protein to enhance the potency and duration of this immune response. The idea is that the treatment will eliminate the primary tumors and prevent or delay cancerous spread to other organs. We will test our strategy in the laboratory and in dogs with bone cancer in a clinically realistic setting, which will provide avenues to move our findings more quickly to human patients who will ultimately benefit from this therapy.

Andrei Thomas-Tikhonenko, Ph.D.

Funded by the Dick Vitale Gala

Over the past several decades, there has been a steady increase in cure rates in children with the so- called B-cell acute lymphoblastic leukemia (B-ALL), a type of blood cancer. Yet many B-ALL patients who failed the initial chemotherapy still die from their disease. Five years ago many of these high-risk patients began to benefit from immunotherapy, whereby patients’ own immune systems are trained to recognize and destroy the leukemic cells. One common form of immunotherapy is based on recognition of CD19, a protein residing on the surface of most leukemic cells. However, even this breakthrough treatment fails in about a third of patients, suggesting that other leukemia proteins need to be targeted in parallel. One alternative protein target is called CD22. CD22-directed immunotherapies show promise, but are not without their own record of failures. Our previous studies led us to believe that one common cause of treatment failure is improper assembly of the CD22 protein, resulting in re-shuffling of its key parts called ectodomains. This re-shuffling could result in CD22 becoming unrecognizable to the immune system. On the other hand, improperly assembled CD22 could be targeted using a new type of immunotherapeutics, which are trained to recognize improper junctions between ectodomains. The proposed work will test these ideas using leukemic cells grown in Petri dishes and in mice and samples from ongoing clinical trials. It will also extend our current studies to other cell surface proteins. In the end, the TVF-funded work would lead to a more precise matching of future patients to best possible treatments and thus much better outcomes.

Erica Stringer-Reasor, M.D.

First year of this Vintner Grant funded by the 2018 V Foundation Wine Celebration in honor of Suzanne Pride Bryan

Approximately 20-25% of breast cancers express the human epidermal growth factor receptor 2 (HER2). These tumors are associated with a high risk of recurrence because of possible resistance to HER2-therapies. Therefore, new therapies are needed to treat this fast growing form of breast cancer.

Poly (ADP-Ribose) polymerases (PARP) inhibitors have been used to treat breast and ovarian cancers with DNA mutations.  In addition to its roles in DNA damage repair, PARP1 has other roles such as activation of genes, which control tumor cell growth.   PARP inhibitors may be used as a treatment to block tumor cell growth.  In this study, we will determine the safety and effectiveness of combining the PARP inhibitor niraparib with the HER2-targeted agent trastuzumab to treat HER2+ breast cancer in a clinical trial. We will also examine tumor tissue samples to help us understand how the treatment effects tumor response. Our goal is to develop better therapies to improve the survival of breast cancer patients who are at high risk of relapse.

Elliot Stieglitz, M.D.

Funded by the Dick Vitale Gala

JMML is a type of blood cancer that affects infants and young children. The cancer cells cause children with JMML to experience belly pain, have difficulty breathing, and be more likely to have bleeding problems. The only way to cure JMML is to kill off every blood cell using harsh medications, and then use someone else’s healthy blood cells as a replacement, known as a stem cell transplant. This treatment causes many side effects like vomiting, hair loss, and can lead to serious infections. Equally upsetting is that this intensive treatment only works half the time with few children surviving if the transplant does not work.

Over the past several years, we have developed lab tests that predict which patients are likely to respond or not respond to this type of intensive treatment. The first aim of this grant is to turn our research test into a clinical test that can be ordered by any doctor around the country to help them decide how to treat their patients with JMML. Our second aim to test two different, new and safer medications in mice to see what the best way is to combine them. Lastly, the overall goal of this grant is to start a trial that uses the clinical test that we described in our first aim to help pinpoint the patients that will benefit from the two medications in our second aim. We expect that by adding these medications we will improve the lives of children with JMML.

Frank Slack, Ph.D.

Diffuse Large B-cell lymphoma (DLBCL) is a common cancer in the US, causing tens of thousands of deaths each year and their incidence is on the rise. MicroRNA regulate the use of other genes and they are frequently mutated in human cancer One of these, miR-155 has been shown to be overproduced in several different lymphoma types, including cutaneous T-cell lymphoma (CTCL) and diffuse large B-cell lymphoma (DLBCL). This miRNA is an excellent target for therapy in DLBCL. miRagen Therapeutics, Inc. is currently testing the safety and efficacy of an inhibitor to miR-155 in patients with CTCL and DLBCL. This is an entirely novel class of drug, and as such requires some research into the parameters for successful delivery and monitoring. In this proposal we seek funding to allow studies that would support these clinical trials. We propose to identify biomarkers to help stratify patients to enroll in the clinical trial, biomarkers of response, and to determine the best route of delivery and the best source of tissue for miR-155 detection.