Identifying New Therapies and Therapeutic Targets in Gastroesophageal Cancer
Abstract
This proposal is for the fiscal year 2022 Peer Reviewed Cancer Research Program (PRCRP) Topic Area and overarching challenge: Gastric and esophageal cancer; Transform cancer treatment through the identification of new targets, especially for advanced disease and metastasis. Note that this cancer and major need are both specifically highlighted in the PRCRP funding opportunity W81XWH-22-PRCRP-IPA. Stomach and esophageal cancers are devastating diseases. The average 5-year survival rate for patients diagnosed with advanced stomach or esophageal cancer is only 5 to 6%. In 2022, it is estimated that there will be 20,600 new patients with esophageal cancer and 16,400 deaths, and 26,400 new patients with stomach cancer with 11,100 deaths in the U.S. Notably, deaths from these two cancers exceed deaths from ovarian cancer (12,800 in 2022), yet advances in our understanding of these cancers and the development of new therapeutics lags far behind. As a result, despite advances in chemotherapy and immunotherapy, there has been little improvement in patient survival. Thus, there is an urgent need for new therapies for these devastating diseases. In our proposal, we will address two fundamental problems. First, finding new therapies that have immediate clinical potential for a specific subtype of stomach and esophageal cancer; and second, finding new targets for drug discovery efforts. It is important to note that even though these cancers arise in different parts of the body, the esophagus and stomach, these two organs are highly related and interconnected. Not surprisingly then, these two cancers have a high degree of similarity, and therefore, we want to study them together. These two cancers are known as GE cancers, gastric and esophageal cancers. Across many cancers, we now know that certain mutations in human genes in cancer cells turn ON the growth of normal cells and make them cancer cells. We also know that if we can create cancer drugs that specifically turn OFF such genes, we often see dramatic therapeutic benefit. This is the essence of the so-called targeted-therapy or precision-medicine revolution. Mutations or alterations in the KRAS gene are the single most common genetic alteration in human cancer and occur in 14% of GE cancers. Importantly, there has been an explosion of new drugs entering clinical trials that inhibit KRAS or inhibit other related genes in the so-called KRAS pathway. For example, adagrasib and sotorasib are drugs that block a mutant form of KRAS and are now FDA approved in lung cancers having KRAS mutations. Despite these advances very little has been done to determine whether these new drugs will work in the GE cancers that have KRAS gene alterations. We will address this in Aim 1. If we are successful, clinical trials of these drugs would start in the very near term. What about the rest of these cancers that do not have KRAS alterations? Here, we desperately need new drug targets that can be pursued for new drug discovery efforts. In the human genome, many genes come as pairs of genes so that there are back-up copies of the most important genes. This makes the human genome stronger, but makes it harder to study these genes in the laboratory because we would need to eliminate both genes (the technical term for these genes is paralog genes). We have developed new CRISPR gene-editing methods that allow us, for the first time, at large-scale to precisely eliminate both copies of a given gene pair. We believe this will lead to the discovery of new drug targets. If we are successful in this (Aim 2), we will be able to identify new drug targets and inform the biopharmaceutical industry of these targets for the creation of future drugs. Lastly, our proposal is unique in bringing together two highly complementary investigators and two outstanding institutions. Sandra Ryeom, Ph.D., is an expert in GE cancer with a collection of 80 patient-derived GE cancer c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310842
Entities
People
- William R Sellers
Organizations
- Broad Institute
- United States Army