Jacob Kaufman, Ph.D. is Assistant Professor at James Cancer Center at Ohio State University
I am committed to a career focused on basic and translational research to improve the treatment of lung cancer. Specifically, I have applied integrated multi-omics analyses and various experimental approaches to characterize gene expression profiles, signaling pathways, and drug sensitivity patterns exhibited by lung adenocarcinomas that have lost the LKB1 tumor suppressor. This gene, a serine-threonine kinase also known as STK11, is lost in approximately 30% of lung adenocarcinomas. And this same gene has recently been shown to confer clinical resistance to immunotherapy.
My current work applies high throughput functional genomics approaches to model systems of LKB1 loss with the goal of
1) identifying novel clinical targets for LKB1 deficient lung cancer, and
2) discover mechanisms of resistance to immune checkpoint inhibition in this subset of tumors.
I completed my Ph.D. in Cancer Biology in 2013 under the mentorship of David Carbone, and after finishing my medical training at Vanderbilt, I completed residency and fellowship at Duke University Medical Center through the ABIM research track pathway (PSTP). During the three research years of my fellowship I worked in the lab of Kris Wood to gain expertise in functional genomics approaches to inform translational and mechanistic questions in cancer biology. Having now completed my Oncology fellowship I will next join faculty at the James Cancer Center at Ohio State University as an assistant professor.
My work will be initially supported by a generous start up package through my first five years at OSU while independent grant funding is being secured. Here I will again work closely with Dr. Carbone, who will serve as my primary clinical and research mentor, and I expect to gain tremendously from collaborations through the cancer center including their excellent thoracic team, outstanding immunotherapy expertise through the Pelotonia Institute of Immune Oncology, and leaders in genomic and proteomic analysis.
My primary focus beginning with my graduate work has focused primarily on characterizing the effects of LKB1 loss on alterations in gene expression, protein expression, mutational and other phenotypes in lung cancer and efforts to use these data to identify biologically significant differences between LKB1 mutant an LKB1 wild-type lung cancer that could lead to precision therapeutic approaches in these tumors.
I identified a gene signature of LKB1 loss that can be used as a biomarker for this genotype, detecting additional cases of functional LKB1 loss beyond those found to have somatic mutations. I used this gene signature to identify associations with drug sensitivity, determining that LKB1 loss directly influences sensitivity to small molecule inhibitors of the MEK pathway.
Evaluating synergy between LKB1 and ATM loss in dictating immune response and differentiation state in NSCLC. Lung cancer is the leading cause of cancer death in the United States. Historically, advanced metastatic lung cancer had a 5% rate of survival at five years but this figure has been steadily increasing over the past ten years as new treatments have become available. Much of the improvement comes from advances in the field of ‘Immuno-Oncology‘ – novel treatments that activate the immune system to attack and control cancer. However, not all cancers respond well to these treatments, and multiple studies have shown that cancers with mutations in the LKB1 gene are inherently resistant to immunotherapy.
We have identified a specific subset of tumors with LKB1 loss that exhibit especially low levels of immune activation. These tumors exhibit many unusual molecular features that suggest that their biology is quite different from other tumors. In particular, they express high levels of genes associated with neuroendocrine differentiation and also frequently have inactivating mutations of a second gene “ATM” occurring in conjunction with LKB1.
Our analysis suggests that pathways regulating tumor differentiation and neuroendocrine features are likely to be linked to mechanisms of immune resistance and that LKB1 and ATM affect these processes, through unclear mechanisms. The goal of the work proposed is to gain understanding of these mechanisms, in hopes that this may allow the future development of novel treatment approaches to improve outcomes in these patients.