State: Pennsylvania

The V Foundation MRA Young Investigator Award

Co-funded with The Melanoma Research Alliance

Although significant progress has been made treating melanoma and the recent approval of several drugs for the treatment of advanced disease, several challenges remain.  For example, clinical responses are generally short-lived as tumors quickly become drug resistant and patients relapse. Moreover, tumors can develop drug resistance through a diverse number of molecular mechanisms, making the development of second-line therapies extremely daunting.  Therefore, it is critical to identify therapeutic targets that are common to the majority of resistant tumors.  We have recently found that a protein kinase called S6K is activated in melanomas resistant to BRAF and MEK inhibitors.  Moreover, we showed that inhibition of this protein using a triple drug combination blocked the growth of resistant tumors.  This provides strong rationale for establishing S6K as a novel target for melanoma therapy.  Notably, S6K is a common node for most resistance pathways.  We propose to investigate the role of S6K in melanoma and determine the therapeutic value of targeting this protein.  Towards these goals we will determine the consequences of blocking S6K in melanoma, identify the proteins that are regulated by S6K and use this knowledge to delineate combinatorial approaches that can lead to long-term tumor remission in a large number of melanomas, including those resistant to BRAF and MEK inhibitors.  We expect that the data generated by these studies can be quickly translated into new strategies aimed at maximizing the therapeutic efficacy of MAPK inhibitors in melanoma and provide actionable information that will guide the design of future clinical trials. 

Funded by 2017 BRCA Fund-A-Need

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.

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.

Funded by 2017 BRCA Fund-A-Need

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.

Funded by Bristol-Myers Squibb

Cancer therapy has undergone a revolution in recent years as a result of the success of several immunotherapies, providing hope to patients with once-thought incurable cancers. One of the most powerful technologies is engineered T cell therapy. By reprogramming a T cell, a type of immune cell, to recognize and kill a cancerous cell, we have seen remissions in over 90% of children and young adults with very resistant acute lymphoblastic leukemia (ALL). Because T cells are living cells, they have the potential to last in the body for months or years and may provide long-term disease control. While most of these remissions are long-lasting, with 60% of responding patients still in remission at 1 year, relapse remains the key mode of treatment failure. One of the reasons for relapse is short lifespan of the engineered T cells in some patients. In this study, we will ask why T cells live many months to years in some patients while they live only weeks to a few months in others. We will use this information to open a clinical trial to test the combination of engineered T cells with a medication to augment T cell function. As we improve on the percentage of long-term remissions, we hope to not only increase the chance of cure but also reduce the number of patients who require intensive therapies, including bone marrow transplant.

Funded by Hooters of America, LLC

African Americans often do not take part in research.  To raise the community’s knowledge about breast cancer research, we will work with trusted members of the community through our Community Ambassador Training (CAT) program.  We will craft a training about the value of research and what it means to take part in research.  The training will build on their current knowledge through activities that highlight breast cancer.  Once trained, Community Ambassadors will take the information to the community spreading the word about the value of research.

Funded by WWE in honor of Connor’s Cure

Brain cancer is now the No. 1 cause of cancer-related deaths in children. A tumor known as pediatric high-grade glioma (PHGG) is the most deadly type. Even though children with PHGG get intense treatment, including surgery, radiation, and chemotherapy, most patients still die within two years of their initial brain cancer diagnosis. Part of the problem is that PHGG tumors are not all the same. However, our research has recently identified a clear group of PHGG tumors in which there is damage to the system of proteins that promote healthy cell growth. The system is supposed to work like the accelerator and brake pedals of a car, allowing the body to keep cell growth in control; but when gene mutations produce bad proteins, the system behaves as though the accelerator is stuck and the brakes have failed. The system becomes overactive and promotes unstoppable tumor growth. This system, called PI3K/AKT, is also a factor in many other aggressive cancers. We think that restoring the proper function of PI3K/AKT is possible and could halt or even shrink PHGG tumors. Our proposed research will test and validate new therapies to do this.