The AACR Gertrude B. Elion Cancer Research Award is open to tenure-track scientists at the level of assistant professor, who completed postdoctoral studies or clinical research fellowships no more than four years prior to the start of the grant term.
Matthew Vander Heiden, MD, PhD
Assistant Professor, Department of Biology, Massachusetts Institute of Technology-Koch Institute for Integrative Cancer Research, Cambridge, MA
The Role of Serine Metabolism in Melanoma
Better models to study cancer metabolism in vivo are needed to target altered cell metabolism for cancer therapy. Serine production from glucose is a particularly important metabolic pathway in human cancers. The gene encoding the first enzyme of the serine biosynthesis pathway, PHGDH, is amplified in human melanoma and allows these cancer cells to increase serine synthesis. To study this metabolic alteration, a mouse model will be generated to control PHGDH expression and study the impact of increased serine synthesis on melanoma progression and metabolism. In this model, the PHGDH allele will be crossed with a mutant BRAF allele to recapitulates the same genetic events observed in the human disease. This model will be used to determine whether PHGDH is required for melanoma initiation and/or maintenance, and to study how increased serine biosynthesis influences cell metabolism to promote melanoma tumor growth. In these studies, state of the art isotope tracer methods will be employed to study how increased serine synthesis contributes to tumor progression and determine how this pathway should be targeted in the clinic.
Top of Page
Sandra S. McAllister, PhD
Assistant Professor of Medicine, Brigham and Women's Hospital, Boston, MA
Elucidating the Pathophysiology of Disseminated Tumor Cells
"Recurrent disease in the form of metastasis affects approximately 30 percent of breast cancer patients and is usually incurable. Clinical evidence indicates that in patients with metastatic breast cancer, tumor cells that disseminate throughout the body can remain undetected for months, years, or even decades following surgery to remove the primary tumor before the patient becomes symptomatic. Preclinical models have shown that less than 1 percent of all disseminated tumor cells (DTCs) is able to form an overt tumor, suggesting that successful DTCs are rare. Nevertheless, these are the cells that claim the lives of breast cancer patients with metastatic disease. Various technologies have been developed to isolate circulating and disseminated tumor cells from the blood and/or bone marrow of cancer patients; however, we currently do not know what distinguishes life-threatening DTCs from the vast majority of otherwise inconsequential DTCs. Hence, we cannot accurately predict whether these patients will experience recurrent disease. The ability to detect and target harmful DTCs before they develop into life-threatening tumors could save many lives. With the support of the Gertrude B. Elion Cancer Research Award, we are initiating a project to identify life-threatening, “consequential” DTCs among heterogenous populations of total DTCs in our unique breast cancer metastasis xenograft model. We are using a novel molecular tagging and detection technology developed by our collaborator, Dr. Channing Yu, that enables us to track the fate of individual DTCs and study rare metastatic events in vivo, which has previously been impossible to do. We will thus isolate DTCs at different phases of metastatic progression and obtain molecular profiles of inconsequential DTCs as well as consequential DTCs both before and after they form overt tumors. As such, we are in a position to obtain information about DTCs that are poised to become successful metastases and learn precisely how they are altered when they convert from a state of indolence to one of malignant growth. Our studies serve as a necessary prerequisite for more accurate identification of breast cancer patients who would benefit from systemic adjuvant therapy to treat potentially deadly DTCs before they develop into incurable metastases."
Top of Page