This week we profile a recent publication in Nature Communications from Dr. Caitlin Nichols and Dr. William Gibson,
and co-led by Dr. Brenton Paolella and Dr. Rameen Beroukhim at Dana-Farber and the Broad Institute.
Can you provide a brief overview of your lab’s current research focus?
Our research focus is twofold. First, we aim to understand better how chromosomes get altered structurally with rearrangements or changes in copy number in cancer; why some of these alterations are enriched across different types of cancer; and the implications of these alterations both on how cancers arise, and progress and on potential treatment approaches that exploit these genetic alterations. These types of events are not only among the most common events in cancer, they also affect far more of the cancer genome than does any other type of somatic genetic event—one-third of the genome in the average cancer.
Our second focus is to understand better how brain cancers arise and progress, and therapeutic approaches that might improve their outcomes, with an emphasis on using genomic technologies to systematically explore these cancers. I am an oncologist and my clinical focus is treating people with brain cancers; I find the devastation these cancers can cause to be deeply upsetting.
What is the significance of the findings in this publication?
I am quite excited about our recent paper on targeting loss of heterozygosity in cancer. About one out of every six genes loses one of its two alleles in the average cancer, representing a profound difference between cancer and normal cells that has not been sufficiently exploited therapeutically. Because of this loss of heterozygosity, normal cells have a more diverse repertoire of alleles to rely on than cancer cells. In the case of genes that are essential to cell survival, the result is that, if we can inhibit the allele remaining in the cancer cells while leaving the other allele functionally intact, we might kill the cancer cells without harming normal cells. We call these GEMINI vulnerabilities, and our paper represents the first systematic exploration of which common alleles in the population might be exploited in this fashion. We thereby detected over 5000 variants across populations that could serve as therapeutic targets if the genes in which they occur could be inhibited in an allele-specific fashion. An accessible presentation of the concepts of our study can be found here.
What are the next steps for this research?
The next steps really are to go through this list of variants to identify ones that could be most straightforwardly inhibited in an allele-specific fashion, either through the development of allele-specific small molecule inhibitors or therapeutically tractable genetic approaches, in a therapeutic discovery platform.
This work was funded by:
I would especially like to thank several foundations that supported the work, including the Gray Matters Brain Cancer Foundation, the Sontag Foundation, the Pediatric Brain Tumor Foundation, Alex’s Lemonade Stand Foundation, St. Baldrick’s Foundation, and the Friends of DFCI, as well as the National Institutes of Health for their generous support.
