The AACR-Genentech BioOncology Fellowship for Cancer Research on the HER Family Pathway provides funding to postdoctoral and clinical research fellows working at an academic, medical or research institution who will be in the first, second or third year of their postdoctoral training at the start of the grant term. Proposed research projects must have direct applicability to the HER family pathway (basic, clinical, translational or epidemiological cancer research).
Sadhna Vora, M.D.
Oncology Fellow, Massachusetts General Hospital, Boston, MA
Fructose Metabolism as a Mechanism of Resistance to Pi3k Inhibitors
“Various components of the phosphatidylinositol 3-kinase (PI3K) pathway are deregulated across a spectrum of human cancers. Therefore, there have been great efforts to develop PI3K inhibitors, and many agents including isoform-specific PI3K inhibitors, pan-PI3K inhibitors, and PI3K/mTOR inhibitors, have entered the clinic. Although initial responses have been observed in PIK3CA and HER2 amplified cancers, resistance emerges, thereby limiting the benefit from these drugs.
"Given that the PI3K pathway plays a pivotal role in cancer metabolism, we hypothesized that cancers with acquired resistance to PI3K inhibition exhibit metabolic deviations relative to sensitive cancers. The PI3K pathway plays an important role in cellular metabolism, in particular glycolysis. Akt is known to stimulate glycolysis by increasing glucose uptake via the increased expression and translocation of glucose transporters and via activation of key glycolytic enzymes including hexokinase and phosphofructokinase 2. Additionally, mammalian target of rapamycin (mTOR), a downstream target of PI3K— is a central regulator of metabolism.
"Our work thus far has revealed novel metabolic alterations that develop as cancers become resistant to PI3K inhibitors, specifically a marked induction of a fructose specific transporter in resistant cell lines as well as decreased glucose uptake and rates of glycolysis. The aim of this grant proposal is to explore metabolic changes that arise from acquired resistance to PI3K inhibitors in HER2 amplified breast cancer, with a focus on determining if altered glucose metabolism opens up new possibilities for therapeutic intervention in cancers with acquired resistance to this novel class of agent.
"I am grateful and honored to receive the AACR-Genentech BioOncology Fellowship for Cancer Research on the HER Family Pathway, which will make this research possible and support my career as a physician-scientist in oncology. I am also thankful to Dr. Jeff Engelman for his mentorship in this area of research.”
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