State: Pennsylvania

Funded in Collaboration With

Stand Up To Cancer (SU2C)

Pancreatic ductal adenocarcinoma (PDAC) is a common and increasing cause of cancer death in the U.S.A. While attempts to harness the immune system to fight cancer has been successful in the treatment of many cancers, these strategies have to date been ineffective in PDAC. PDAC tumors contain not only cancer cells but a dense layer of fibrous tissue, called stroma. The stroma interferes with the immune systems ability to attack PDAC both by releasing substances that inhibit the immune system and by acting as a physical barrier to immune cells reaching the cancer cells. We have recently shown that Vitamin D can act on PDAC tumors to prevent the stroma from releasing immune inhibitory substances and to facilitate immune cell entry into tumors, potentially setting the stage for a more effective immune attack on PDAC. In this proposal, the post-doc/clinical fellow will work closely with a team of physicians, cancer immunologists, and computational biophysicists will work together to improve the effectiveness of immunotherapy for PDAC. The post-doc/clinical fellow will contribute toward the completion of two tightly coupled aims: first, novel theoretical and experimental tools will be used to characterize the patient-specific immunological environment of PDAC tumors; second, the detailed understanding of the immune environment in PDAC tumors will be used to develop novel immunotherapy strategies that will be tested in a new clinical trial. The clinical trial will use a combination of conventional chemotherapy, a potent Vitamin D analogue, a drug that activates immune cells, and surgery, in an effort to improve the outcomes of patients with pancreas cancer. The Penn post-doc will be the critical individual who supplies operative tissue to the diverse collaborators in the project, and correlates the different genomic and immunologic studies with patient outcomes. As such they will gain knowledge and experience in molecular phenotyping of tumors, immunotherapy, and clinical trials.

Funded in Collaboration With Stand Up To Cancer (SU2C)

Decades of cancer research and therapeutic development have made it clear that achieving durable control of invasive solid tumors requires therapeutic combinations of a large number of drugs that target different elements within cancer cells. In aggressive cancers where cure is achievable (e.g., subtypes of leukemia and lymphoma), as many as 4-6+ drugs may be needed when administered as curative treatment to patients. This is because simpler drug combinations become ineffective due to the development of drug resistance by the tumor.

The guiding hypothesis of this project is that network-based models of cancer cell signaling together with evolutionary analyses and therapeutic data can identify a set of element within cancer cells that might eventually be exploited through therapeutic combinations to achieve a more durable control of cancer, even in the presence of tumor drug resistance. Specifically, we propose a theoretical framework that integrates so-called discrete dynamic network models and control theory with genomic evolutionary approaches. These models will be informed, tested, and iterated using experimental approaches applied to relevant cancer model systems. Based on its exemplary clinical need, we will focus on BRAF-mutant melanoma (skin cancer) and PIK3CA-mutant, estrogen receptor positive (ER+) breast cancer as initial tumor types in which to test and develop our approach. The final result will be a theoretical and experimentally validated approach that can in principle be generalized across many other therapeutic strategies.