NUAK-1, a Novel Target for Appendiceal Cancer Treatment
Abstract
Background: Mucinous adenocarcinomas of the appendix (MAC) constitute a rare type of cancer that affects 1-2 people per million each year in the U.S. Relatively little is known of the specific biology of these cancers. The treatment of choice is surgery, but many patients are not candidates for surgery, because their cancer is too advanced or aggressive. These patients instead receive chemotherapies approved for colorectal cancer, but these frequently have only limited efficacy in MAC. This application will address two listed Focus Areas of Rare Cancers: Biology and Etiology and Therapy. Aim 1 proposes research predominantly centered on achieving a better understanding of MAC biology. Here, we will study whether a protein, NUAK-1, which is present in much larger amounts in MAC than normal appendix is important for MAC cells to divide, survive, and spread. Studies proposed in Aim 2 will be directed at testing the basis for a new therapeutic approach to treating MAC, hence will center on the Therapy Focus Area. We will test specific inhibitors (specifically, the drugs HTH-01-015 and WZ4003) and will also test the efficacy of knockdown with a particular type of RNA (called shRNA, for short hairpin ribonucleic acid) that inhibits gene expression and can be directed to inhibit expression of just one specific gene of choice (in this case, the NUAK-1 gene; see below). Other drugs we plan to test include palbociclib (which inhibits part of the cellular machinery controlling cell replication), MRTX1133 (a drug that inhibits one of the driver mutations that is thought to engender carcinogenesis in MAC and other cancers), and TAK-981 (a first-in-class inhibitor of two entirely different enzymes called sumo activating enzymes 1 and 2). All of these drugs are experimental in MAC, and will be tested for the first time in MAC in this study. Scientific Objective and Rationale: We have identified NUAK-1 as a gene that is expressed at high levels in MAC samples compared to normal appendix. We know that NUAK-1 has important roles in various cellular functions, many of which are relevant to cancer growth. NUAK-1 also promotes tumor growth and spread in some cancers, but has never been investigated in MAC. Since NUAK01 is overexpressed in MACs, we hypothesize that this could constitute a new therapeutic target in MAC. We will test that in this study. Applicability of the Research: This research will help those afflicted with MAC, which have no successful treatment options beyond surgery (where this is still possible). We plan to help these patients in two broad ways: (1) by contributing to a deeper understanding of the biology of MAC; and (2) by testing the basis for a new treatment of MAC that involves inhibiting NUAK-1. Since this protein is expressed at high levels in MAC, we hypothesize that blocking this will constitute a new, effective treatment for MAC. This can be accomplished either by blocking NUAK-1 function or by reducing expression, and we will test both here. Potential Clinical Applications: We don’t yet know whether this strategy will work. There are two possibilities: (1) that NUAK-1 expression is increased in MAC as a result of cancer, rather than as a cause of cancer; and (2) increased NUAK-1 expression is directly required for either tumor development, metastasis, or both. We predict that the second of these two possibilities will be true, hence the therapy should work as planned. The next steps would include detailed toxicity studies to make sure the drugs we will test do not cause undue harm to patients with MAC. Other studies would include pharmacokinetic/pharmacodynamic studies, which are technical studies critical to establish the correct dose that elucidates drug distribution in the body, how long it lasts, how it is excreted, and other features of drug biology. Here, we will mainly focus only on drug efficacy. Risks include potential toxicity, which might even precl
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310757
Entities
People
- Andrew Lowy
Organizations
- United States Army
- University of California, San Diego