THE RIPPLE EFFECT
AGUIRRE DE CUBAS, PHD • ASSISTANT PROF., MEDICAL UNIVERSITY OF SOUTH CAROLINA 2021 FORBECK SCHOLAR
A BREAKTHROUGH IN KIDNEY CANCER
It has been an exciting few weeks for our lab. We recently published a study in Cancer Research demonstrating that kidney cancers harboring mutations in SETD2, one of the most frequently altered genes in clear cell renal cell carcinoma, become highly dependent on the anti- apoptotic protein BCL-xL for survival. This work uncovered a previously unrecognized therapeutic vulnerability that could be exploited to selectively target this subset of kidney cancers.
WE DISCOVERED THAT KIDNEY CANCERS WITH A FAULTY SETD2 GENE DEVELOP A SURPRISING WEAKNESS: THEY BECOME HEAVILY RELIANT ON A PROTEIN CALLED BCL-XL JUST TO STAY ALIVE, CREATING A POTENTIAL DRUG TARGET THAT COULD KILL THESE CANCER CELLS WHILE SPARING HEALTHY ONES. Building directly on these findings, we were recently awarded a new five-year NIH/NCI R01 grant entitled “Exploiting Primed Inflammatory Signaling to Target SETD2-Deficient Renal Tumors.” The grant will investigate how loss of SETD2 rewires inflammatory and mitochondrial signaling to create this therapeutic dependency and will evaluate strategies to translate these discoveries into new treatments for patients with kidney cancer. The support and community provided by the Forbeck Foundation have been invaluable throughout my career, and I am incredibly grateful to share these milestones with the SAB. Please extend my thanks to everyone, and I look forward to staying connected with the Forbeck community.
FOLLOW UP FROM THE 2022 FORUM ON CANCER AND GENOMIC DARK MATTER
In May 2022, Ting Wang, PhD (Washington University in St. Louis) and Kathleen Burns, MD, PhD (Dana-Farber Cancer Institute) chaired a Forbeck Forum on an area many researchers were still overlooking: transposable elements, the roughly 50% of the human genome long dismissed as “junk DNA” or “genomic dark matter.” The Forum brought together 19 speakers, including four Forbeck Scholars, to examine how these repetitive elements directly shape the cancer genome and epigenome–disrupting genes, activating oncogenes, and in some cases triggering immune responses that point toward new therapeutic strategies. At the time, this was largely uncharted territory for cancer research, and the meeting became a launchpad: several participants went on to submit a joint Mark Foundation Endeavor project proposal directly inspired by discussions at the Forum. Scientists are learning to weaponize our own ancient viral DNA against cancer and other diseases, but it’s complicated because the same sequences play important roles in normal biology too. WHERE THE FIELD STANDS NOW Since chairing that meeting, Wang and Burns have organized several follow-on meetings that grew out of the original Forum’s discussions and have published a paper on the topic. What was, in 2022, an unexplored corner of the genome has become one of the fastest- growing areas in cancer research.
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