Intrahepatic cholangiocarcinoma (ICC) is the second most common kind of liver cancer. It is a very difficult disease to treat. Only about one out of ten patients live more than five years after the cancer has been detected. There are several different types of ICC. One important type has changes in a gene called the Fibroblast Growth Factor Receptor 2 (FGFR2). Drugs that turn off FGFR2 cause the tumors to shrink, but the tumors eventually become resistant to the drug and begin to grow again. The goals of this project are to understand what causes drug resistance and to develop ways to prevent it from happening. In this project, we will study samples of tumors from patients who are being treated with drugs against FGFR2. We will also make models that allow us to study ICC in the laboratory. Finally, we will use a method that could allow us to create a new kind of drug that is better at turning off FGFR2. We hope that our work will result in new treatments that help patients with ICC to live longer.
First year of this Vintner Grant funded by the 2018 V Foundation Wine Celebration in honor of Robin Lail
Triple negative breast cancer (TNBC) is breast cancer that lacks HER2 and ER/PR receptors. Because most treatments are based on having these markers, TNBC is hard to treat. Additionally, TNBC often spreads to the brain (brain metastasis), which is even harder to treat. Radiation therapy (RT) is a standard local therapy for TNBC brain metastases; however, survival is less than 6 months.
Immune cells (found throughout the body) fight invaders like viruses, bacteria and cancer. However, cancer cells are highly adept at hiding from immune cells. Immunotherapies are being tested to help immune cells fight cancer better. There have been promising results using immunotherapies to treat brain metastases. We have shown that TNBC brain metastases have a higher number of immune cells called tumor infiltrating lymphocytes (TILs) compared to TNBC in breasts. More importantly, we found that patients with a higher number of TILs in their brain metastases live longer. Adding RT to immunotherapies can help immune cells to fight cancer. We will use mouse models to test this strategy, which will lead to a clinical trial in humans. We expect immunotherapy will also treat cancer inside and outside of the brain at the same time, which will improve the lives of patients facing this disease. We also want to find more signals in brain metastases (biomarkers) that will guide selection of the right immunotherapy for each patient. New biomarkers will help us treat the right patient, at the right time, in the right way, with immunotherapies.
Funded in partnership with Miami Dolphins Foundation
Having an unhealthy weight increases one’s chance of getting cancer. It also increases the chance of dying in people who already have cancer. Keeping a healthy weight is important, especially for people from Hispanic and non-Hispanic black families who have a high chance of having an unhealthy weight. A program that helps cancer survivors lead their children and grandchildren in keeping a healthy weight may help them make their own health better and may also make their children’s and grandchildren’s health better. If the program uses smartphones and tablets, it may help connect family members who are different ages. The goal of this project is to develop and test a program that uses the Internet and mobile devices to help Hispanic and/or non-Hispanic black female cancer survivors lead their families in keeping a healthy weight. The first part of the project will develop the program by getting feedback from Hispanic and non-Hispanic black female cancer survivors. The second part of the project will test the program to determine if it is possible, well-liked, and shows improvements on the weight, physical activity, and diet of cancer survivors, their children, and grandchildren.
Inhibitors of the poly(ADP-ribose) polymerase enzymes (PARPi) represent a significant advance in ovarian cancer treatment, particularly in those with inherited BRCA1 and BRCA2 mutations. These drugs are taken by mouth, are effective, and generally have fewer side effects than chemotherapy. However, responses to PARPi are generally limited and cancers develop treatment resistance. Inhibition of the ATR kinase offer a promising solution to this problem. Inhibitors of ATR (ATRi) and PARP have distinct and complementary effects. Data from our group shows that the PARPi-ATRi combination causes complete tumor regression in BRCA2-associated ovarian cancer animal models, an effect that is superior to that observed with PARPi alone. Based on these data, we plan a clinical trial of the PARPi, olaparib with an ATR inhibitor in patients with ovarian cancer. With support from the V Foundation, we have set out to further improve this therapeutic strategy. First, we will study tumor tissue from patients enrolled on the clinical trial to identify markers that predict if the treatment will be effective. Furthermore, we will use tumor tissue from patients to create animal models and use these animal models to test ATR inhibitor combinations with different PARP inhibitors, in addition to olaparib. We will determine which PARPi is most active in combination with ATRi, particularly in the BRCA1/2 mutation subset. Finally, we will use novel protein-based techniques to better understand exactly how the ATR and PARP inhibitors work together, which will permit further improvements of this therapeutic strategy. Our goal is to develop the most effective and well-tolerated treatment of BRCA1/2-mutant ovarian cancers for which standard therapies have faltered.
Children with diffuse midline gliomas continue to have a dismal prognosis and most children die within one year of their diagnosis. Decades of clinical research and hundreds of clinical trials have not been able to change the outcome for these patients. Studies have shown that the majority of these tumors carry a specific mutation referred to as H3.3K27M which is present in almost all tumors cells making this a very attractive target for immunotherapy approaches.
Within this proposal we are aiming to assess the benefit of a specific immunotherapy approach referred to as T cell receptor approach. We have been able to show in the laboratory that this approach is able to kill H3.3K27M tumor cells very effectively. Based on our exciting animal data, we propose to test this new therapy approach in clinic. Subjects whose tumors carry the H3.3K27M will undergo collection of their own T-cells prior to start of radiation therapy, which is considered the standard of care for these tumors. These T cells will subsequently be modified in the laboratory to specifically recognize the specific H3.3K27M mutation. These modified T cells will then be given back to subjects once they completed radiation therapy.
Within this project we will assess if such a therapy approach is feasible and safe. This project has the potential to significantly impact the treatment approach for a disease for which we have not achieved any improvement for the last several decades and is the first of its kind for this devastating disease.
Funded in partnership with the American Kennel Club Canine Health Foundation
Bladder cancer or urothelial carcinoma (UC) affects approximately 40,000 dogs per year in the US with specific breeds including Scottish Terriers, West Highland White Terriers, Shetland Sheepdogs, Beagles, and Parson Russell Terriers being over-represented. Affected dogs usually display lower urinary tract clinical signs including bloody urine, frequent urination, difficulty and pain on urinating, and urinary outflow tract obstruction. Standard of care consists of anti-inflammatory drugs either alone or in combination with chemotherapy or radiation therapy. While these treatments can lead to stable disease for 6-12 months, they rarely lead to a cure, and most dogs eventually succumb to their disease. In human medicine, urinary bladder tumors have been shown to exhibit a high gene mutational burden which directly correlates with a favorable response to immune therapies. Canine UC exhibits a similar mutational load suggesting that the disease in dogs may also be immune responsive. In this study, the investigators will evaluate the safety and effectiveness of a novel targeted, immune therapy that aims to promote a powerful immune response against a specific gene mutation (V600E B-Raf) recently identified in up to 87% of dogs with UC. The investigators hypothesize that vaccine-induced anti-tumor immune responses will lead to tumor regression and that such favorable responses will correlate with the baseline mutational burden of the tumor. The investigators will use standard immunological methods and advanced genetic sequencing technology to study systemic and intra-tumoral immune responses to identify biomarkers that may predict immunological and clinical response in dogs.
My research interest is cancer genetics with an emphasis on clinically relevant questions that will improve our understanding of the cancer genetics of clinical phenotype and simultaneously improve patient care in oncology. I have extensive bench research experience in the fields of genome sequencing technology development, human genetic analysis through human genome sequencing and molecular assay development. My research benefits from the various innovations in genomic and genetic technologies that my group has developed.
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.
When an individual is born with one mutated (or abnormal) copy of BRCA1 or BRCA2, there is a high chance that they will develop cancer. Drugs called PARP inhibitors have been developed to take advantage of DNA repair deficiency in BRCA related cancer, but they do not work in all patients, and resistance to the medications frequently develops. There is a pressing need to more deeply analyze primary tumors in BRCA1/2 mutation carriers to see how often there are “subclones” that have other types of primary resistance to PARP inhibitors and other therapies. This information will be critical to rationally design new strategies that will overcome a broad spectrum of resistance mechanisms. Due to a higher burden of DNA mutations in BRCA1/2 related tumors, there is significant excitement about the prospect of using immune therapies for these cancers. However, further research is needed to understand the baseline immune status of BRCA1/2 tumors and the pathways in which the immune system can be turned ‘on’ in these tumors. We propose a novel strategy to use inflammatory and immune responses that target both sensitive and resistant cells within a tumor.
To address these important objectives, we present two integrated aims that utilize our collective expertise in cancer genomics, DNA repair, tumor immunology, and mouse models of cancer. Consistent with the goals of the Team Science Convergence Award application, researchers from multiple schools, departments and divisions at the University of Pennsylvania will work together to maximize innovation and productivity.
The goal of this project is to provide women with BRCA2 mutations with a better option for reducing their risk of breast cancer while managing the menopause symptoms caused by removal of their ovaries. After ovaries are removed, BRCA2 carriers must balance management of menopause symptoms against high risk of primarily hormone-driven breast cancers, without much data about the long-term safety of hormone replacement. A new combination of bazedoxefine,a tamoxifen-like medication, and conjugated estrogen (BZA/CE or Duavee® ), has been extensively studied in postmenopausal women (without mutations) with established safety data . BZA/CE should reduce breast cancer risk without compromising quality of life for BRCA2 carriers by causing menopausal symptoms, bone loss or uterine problems. The randomized clinical trial compares BZA/CE to CE alone for 3 months in women carrying a BRCA2 mutation soon after ovary surgery. Their breast tissue will be examined to assess whether, as predicted, the BZA/CE has protective effects against breast cancer compared to the CE alone. After 3 months, the study is unblinded so those on CE can take a short course of progesterone. The exciting part of the project is all of the novel science that will be applied to assess the action of BZA/CE and CE on normal breast tissue in women with BRCA2 mutations. This has not been very well-studied, and is critical not only for breast cancer prevention but also for potential therapeutic implications for the cancers BRCA2 mutation carriers can develop.
