V Scholar Archives - Page 38 of 62

Pancreatic cancer is one of the most deadly diseases in the U.S. It is hard to diagnose early, and it does not respond to treatments when discovered late. Therefore, new methods for early diagnosis and prevention are critical. Currently, our approach to finding cancer biomarkers relies on technologies that lack spatial or temporal resolution for discriminating individual cells and tumor regions. In fact, much of our analyses are based on average measurements from the mixed population of different cell types within the tumor tissue. This means that each biomarker has to be validated in multiple experimental and pre-clinical settings through very time-consuming and expensive processes, severely hampering our ability to discover diagnostic or therapeutic biomarkers. We developed a novel method to image and sequence DNA and RNA genome-wide without extracting them from the tissue, and the nucleic acid sequence is visualized directly under the microscope. Therefore, we combine positional features associated with cancer progression and molecular or genetic features associated with cancer clonal evolution. Our proposal will determine genetic sequences associated with each pixel of cancer tissue images to generate a map of genetic alteration and biomarkers as a function of the tissue landscape. If successful, our proposal could signal a new approach to discovering genetic biomarkers using specific architectural hallmarks of cancer, rather than average gene expression differences between heterogeneous tissues.

Steven Barthel, Ph.D.

The precision oncology approach to the treatment of cancer bases treatment decisions on the biology of an individual’s cancer, most often using genetic alterations or mutations to inform therapy. This approach has been successful in a few cancer types, including lung cancer, melanoma, and chronic myelogenous leukemia where oral targeted therapies have led to both improved patient outcomes and fewer side effects compared to standard chemotherapy. However, this approach has not yet realized its full potential in these or other cancer types. In this proposal we plan to study new cancer-causing gene mutations involving the NTRK1, NTRK2 and NTRK3 genes, which are found in numerous types of cancer. We have already demonstrated that tumor cells treated with targeted therapies against this gene family can kill cancer cells in the laboratory. We have also observed early and dramatic tumor shrinkage in patients with different tumor types that share mutations in these NTRK genes. This proposal will focus on determining additional mutations of NTRK genes that may respond to therapy. The proposal will also study how cancer cells become resistant to targeted therapies and develop new laboratory models of NTRK+ cancer to develop new therapies for these cancers.