Melanoma and Imaging
We have developed a system to reproducibly induce spatially controlled endogenous BRAFV600E/PTEN-null melanoma that can be used with intravital imaging to visualize tumor progression. This is the first true known model of melanoma metastasis, as we can generate local endogenous tumors that consistently metastasize to distant organs. With intravital imaging, we plan to use this model to directly visualize how melanoma progresses from single cells and to investigate heterogeneous tumor response to targeted therapy.
Mouse Pre-Clinical Testing
Through collaboration with Dr. Kwok Wong of Dana Farber Cancer Institute recently published in Nature, we demonstrated that “co-clinical” mouse trials performed concurrently with human studies can provide valuable insight into the interpretation of the human studies. These murine studies in faithful genetic tumor models allow human clinical testing to be more efficient, reducing the risk of experimental trial to participant patients. While the published study involved lung cancer and the genetic modifiers of that disease, the concept of murine co-clinical trials is being applied to many other cancer types in the UNC MP1U and elsewhere.
Reprogramming of Breast Cancer in Response to a Targeted Therapy
Through a close collaboration with Dr. Gary Johnson, Kenan Professor and Chair of the UNC Department of Pharmacology, we published a manuscript in Cell that shows extensive remodeling of kinase signaling in breast cancers when such tumors are treated with therapeutic kinase inhibitors. This report employed a novel technology developed by Dr. Johnson to measure the activity of hundreds of kinases in a cancer simultaneously, and was validated on MP1U models. While the technology will be very important in future drug development efforts, we believe the finding of this rapid cellular reprogramming in response to therapeutics represents a critical understanding of how tumors develop resistance to effective therapeutics. This work shows that tumors can rapidly change intra-cellular signaling, likely in the absence of new genetic events, to become resistant to kinase inhibitors, explaining the clinical observation of the rapid emergence of resistant tumors in patients treated with kinase inhibitors for certain solid tumors (e.g. melanoma, lung cancer, breast cancer etc.) We are continuing to work with the Johnson lab to examine other drugs in MP1U models of cancer to explore how tumor resistance develops. This technology is being used in human clinical trials at UNC in breast cancer (PI: Dr. Lisa Carey) and melanoma (PI: Dr. Stergios Moschos).
SRC Family Kinase Inhibitors and Melanoma
In a paper recently published at Cancer Cell, the Sharpless lab showed that loss of a commonly mutated cancer gene, LKB1, leads to activation of a family of kinases involved in metastasis (the SRC family kinases, SFKs). Activation of SFKs by LKB1 loss in turn greatly enhances tumor metastasis. Since SFKs are enzymes that can be targeted by small molecule drugs, this work established an important role for LKB1 in metastasis of melanoma and lung cancer, and identified a new target for anti-cancer therapy. UNC filed intellectual property related to this work and is negotiating to license this IP to a Portland based diagnostic company.