Identifying the Histological and Molecular Constraints Imposed by Rb During Therapy-Induced Small Cell Transformation
Abstract
Our project tackles the problem of resistance to targeted therapies. As therapies have become better and better at shutting down the cancer causing activity of their target, cancers have added additional ways in which they develop resistance to these therapies. A particularly devastating form of therapy resistance that is becoming more and more prominent is the transformation from one cancer type to another that is not dependent on the original therapeutic target. In the lung, activating mutations in the oncogene called EGFR drive the formation of lung adenocarcinoma (the most common form of lung cancer). Inhibitors, such as osimertinib, that shut down oncogenic EGFR signaling are particularly effective therapeutics. However, resistance to this therapeutic regimen can arise in the form of small cell lung cancer (SCLC), a completely different type of lung cancer that does not require EGFR activity and has extremely poor prognosis. EGFR, together with another cancer gene called RB, most definitely regulate a network of genes that are critical for this cancer type switch, but the identity of the genes in this network is unknown. Our project aims to identify the molecular constraints imposed by oncogenic EGFR and RB during cancer formation and in response to EGFR-targeted inhibition. These genes that govern these molecular constraints that we will identify in this project represent untapped therapeutic targets that when targeted together with EGFR-directed therapies could lead to more durable patient responses and cures because the cancer type switching will be blocked. This project covers multiple Areas of Emphasis: Understand mechanisms of resistance to treatment, Understand the molecular mechanisms of initiation and progression to lung cancer and Identify innovative strategies for the treatment of lung cancer. The timeframe for direct clinical benefit of our research is difficult to predict. This is a discovery and breakthrough project. As such, the potential of our research to impact clinical treatments and patient outcomes is extraordinary. This is true not only in lung cancer, but also in other tumor types such as prostate cancer where a similar cancer type switching paradigm has emerged. Though our research has the potential to touch the lives of all members of our society, it will be particularly impactful for the members of military who suffer disproportionally more from lung cancer-related tragedies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210742
Entities
People
- David M Feldser
Organizations
- United States Army
- University of Pennsylvania