Cancer Genetics Broadens Its Quest
A revolution in cancer began almost 50 years ago when Dana-Farber researcher Frederick Li, MD, proposed that genes can raise the risk of inheriting cancer. The search then expanded to non-inherited (somatic) mutations that cause cancers to develop, and that drive metastasis, drug resistance, and relapse. Now the exploration has broadened from genes to whole genomes, including the vast expanses of DNA outside of genes, some times called 'dark matter' by analogy to cosmological studies of the universe.
Cancer genetics has launched a new therapeutic approach that targets a tumor’s genetic vulnerabilities, and a new way of classifying and treating cancers according to their molecular subtypes rather than the tissue in which they arise. For example, 14 different genetic mutations have been identified in lung cancer so far that have treatment implications. Thus, one lung tumor may have more in common molecularly with a breast tumor than with another lung tumor, with profound implications for treatment choices.
DF/HCC’s large and vibrant Cancer Genetics Program remains at the forefront of this revolution. “Our largest effort is to identify mutations that activate cancer-promoting oncogenes or deactivate genes that suppress tumors,” says David Kwiatkowski, MD, PhD (BWH), who with Levi Garraway, MD, PhD (DFCI), leads the program. “Our ultimate goal is to develop personalized cancer therapy for patients based on the genetic characteristics of their tumor.” To this end, the program is using ‘next gen’ DNA sequencing to rapidly and accurately characterize a patient’s cancer genetic subtype and guide the choice of the best therapy. Eventually, researchers may use cells and molecules circulating in the bloodstream to non-invasively monitor a cancer’s response to therapy and detect drug resistance, metastasis, or relapse – in real time.
Cancer genetics has had its most direct translation into clinical practice in the area of inhibiting oncogenic mutations – like EGFR, BRAF, ALK, and MEK – that promote the unbridled growth and proliferation of tumor cells. A growing roster of inhibitors, or targeted therapies, are either approved – like Gleevec (imatinib) and Tarceva (erlotinib) – or in clinical development.
But one common mutation has eluded inhibition: KRAS, which is mutated in about half of colon cancers and in many tumor types. “Figuring out how to target KRAS is one of the biggest challenges in cancer today,” says thoracic oncologist Jeffrey Engelman, MD, PhD (MGH). Engelman recently developed a new strategy that foils KRAS indirectly by double-teaming what it activates. Mutant KRAS activates the MEK growth signaling pathway. However, MEK inhibitors alone have not proven effective in KRAS mutated cancers, so another gene might be conspiring with MEK to evade cell death. Engelman and his colleagues decided to use MEK inhibition as a backbone for building a combination therapy.
They used a technique called RNA interference (RNAi) to silence the expression of different genes in different cells in an unbiased fashion. They grew these cells with and without exposure to a MEK inhibitor, reasoning that the cells that died with MEK inhibition had lost a MEK co-conspirator gene. This led to the BCL-XL gene, which researchers had previously shown allows cells to override apoptosis, the cell death pathway. Engelman’s team demonstrated in cell cultures and then in mice that inhibiting both MEK and BCL-XL was much more lethal to cancer cells than inhibiting just one or the other. In genetically engineered mouse models of human KRAS mutant cancer developed by Kwok Wong, MD, PhD (DFCI), the combined therapy demonstrated significant activity in shrinking tumors, providing greater support for the promise of this therapeutic approach.
Drugs that inhibit MEK (trametinib) and BCL-XL (navitoclax) are in clinical testing separately, which should accelerate the path toward a combination trial. If this strategy succeeds, it would be a big advance for the many cancer patients with KRAS mutations. Still, it may not benefit