Overview of Research Projects
The Bivona lab is a basic and translational cancer research group investigating the molecular basis of cancer growth and of response and resistance to targeted therapy in lung cancer, and other solid cancers. Using unbiased systematic genetic and pharmacologic approaches and well-annotated clinical samples and datasets, many of which are obtained from our own patients, our group has discovered several novel molecular determinants of targeted therapy resistance in these cancers. Our collaborative studies have provided fundamental insight into the regulation of oncogene signaling in cancer cells and have immediate clinical implications for the improved management of cancer patients. Major contributions have been centered upon the discovery of rational upfront combination therapies (polytherapies) that co-target a particular oncogenic driver protein together with an additional molecular pathway that promotes resistance to targeted therapy acting against the relevant oncogenic driver protein.
The significance of these pioneering studies is underscored by the development of several clinical trials testing the rational upfront polytherapy strategies uncovered by our work to enhance initial response and forestall the onset of resistance in molecularly-defined cancer patient subsets, including those with oncogenic EGFR, ALK, BRAF, and KRAS. Specific examples include clinical trials testing next-generation EGFR kinase inhibitors and ALK inhibitors in combination with small molecule inhibitors of AXL and MEK, respectively, in the first-line treatment setting. Additionally, we uncovered EGFR activation, in some cases acting potentially downstream of YAP1 activation, as a mechanism of resistance to BRAF-inhibitor treatment in BRAF-mutant lung cancer. This has provided the biological rationale for the development of a clinical trial testing upfront BRAF-EGFR inhibitor polytherapy in BRAF-mutant lung cancer patients to forestall resistance. Furthermore, our work has motivated the clinical development of a first-in-class direct inhibitor of NF-kB (RelA) for testing in patients with EGFR-mutant lung cancer in combination with an EGFR kinase inhibitor in the first-line treatment setting to enhance clinical response and prevent resistance. These clinical trials all arose from our laboratory based discoveries, with rapid translation of the research findings into direct clinical impact. Our laboratory and clinical research is pioneering because most efforts in the field to thwart targeted therapy resistance in solid cancers have focused on sequential monotherapy strategies, without substantial success to date. The alternative strategy motivated by our group’s efforts to define upfront polytherapy approaches based upon deep systematic interrogation of the aberrant signal transduction operating in oncogene-driven cancer cells holds great promise to definitely combat or eliminate targeted therapy resistance in solid cancers, and transform them from lethal diseases into chronic or curable conditions.
Please contact us for information regarding specific ongoing research projects in our group.