Sadhna Vora, MD
Massachusetts General Hospital
2012-2013 BCRF Project:
Conquer Cancer Foundation of ASCO 2012 Young Investigator Award (the Hirschhorn Award, in honor of Susan B. Hirschhorn and in memory of her mother, Ellen S. Hirschhorn)
Various components of the phosphatidylinositol 3-kinase (PI3K) pathway are dysregulated across a spectrum of human cancers. Several PI3K inhibitors have entered the clinic, and though responses have been observed, the cancers often start to grow again. The PI3K pathway is central for regulating cellular metabolism, and it is, therefore, likely that cancers that are resistant to PI3K inhibition have altered metabolism in comparison to cancers that are sensitive to PI3K inhibition.
Dr. Vora's initial work in breast cancer has revealed several novel metabolic changes that arise as cancers become resistant to PI3K inhibitors. In particular, in resistant cells, she has observed an induction of a transporter that is known specifically to move fructose into cells. Additionally, she observed decreased glucose uptake and evidence of decreased utilization of glucose in resistant cells. These data suggest the hypothesis that cancers that develop resistance to PI3K inhibitors have undergone metabolic changes affecting how they produce energy or the building blocks necessary for growth, and possibly that fructose may serve some of these functions instead of glucose.
Furthermore, Dr. Vora intends to look at decreased glucose utilization as a biomarker for acquired PI3K inhibitor resistance. Positron emission tomography (PET) scanning is the imaging modality typically used to monitor cancer growth or shrinkage in response to anticancer treatments. PET scanning relies on the fact that tumor cells typically take up glucose at higher rates than normal cells. By utilizing labeled glucose as a tracer, one can image the areas of the body that are taking up glucose at high rates. However, given her preliminary data suggesting that cancer cells with resistance to PI3K inhibitors take up glucose at lower rates than sensitive cells, she will study whether loss of signal on PET scanning correlates with acquisition of resistance to PI3K inhibitors.
The aim of Dr. Vora's BCRF-funded research is to explore metabolic changes that arise from acquired resistance to PI3K inhibitors in breast cancer, with a focus on determining if these metabolic changes open up new ways to monitor disease more accurately as well as possible therapeutic opportunities.
Mid-year Progress: The aim of Dr. Vora's work is to explore in breast cancer the efficacy of a class of therapy called PI3 Kinase inhibitors. These agents work by targeting the PI3 Kinase pathway, which is hyperactive in roughly 30% of breast cancers. While these agents have shown activity in this subset of breast cancer, the length of duration of response is typically less than a year, after which resistance emerges. Dr. Vora is investigating methods of making these agents more effective, lengthening the duration of response and increasing the percentage of tumors that will respond.
Using an inhibitor of glucose metabolism called 2 deoxyglucose in combination with PI3K inhibitor, Dr. Vora observed that some PI3K inhibitor resistant cells become sensitized again. Moreover, she has also noted that glutamine deprivation sensitizes certain resistant cells to PI3K inhibitors. She and colleagues are exploring the use of a glutaminase inhibitor, which blocks glutamine metabolism, in combination with a PI3K inhibitor in their resistant cell lines. Finally, using a technique called mass spectrometry to measure flux through metabolic pathways, Dr. Vora has noted that some resistant cells are able to utilize fructose or glutamine as carbon sources, in addition to glucose. This finding supports their previous finding of upregulation of a fructose specific transporter in our resistant cell lines.
Going forward, Dr. Vora's subsequent steps will be to explore the use of agents that target specific metabolic pathways in combination with PI3K inhibitors to unveil possible therapeutic drug combinations in breast cancer that is resistant to PI3K inhibitors.