Studies of novel antitumor agents for lung carcinoma
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Due to adverse effects of smoking, lung cancer is now the leading cause of death from cancer in the United States. The proportion of tobacco-derived cancers classified as nonsmall cell lung cancer (NSCLC) is increasing and now outnumbers other histological subtypes. Whereas chemotherapy for the other main type of smoking-associated cancer (small cell lung cancer) can be effective, the current therapy for NSCLC has limited efficacy. In part, this is because many patients with NSCLC have metastasis (tumor has spread to other sites in the body) and often relapse with systemic disease after initial treatment.
 
 
 
 
 
 Illudins are natural products with a novel chemical structure isolated from the toxic Jack O’ Lantern, a mushroom which grows throughout California. The mushroom received its unusual name because it glows in the dark in the fall. Our laboratory has been developing novel chemotherapeutic agents from these Illudin toxins for treatment of NSCLC. During the past years, with support from the TRDRP, we accomplished the following in developing a novel chemotherapeutic agent for NSCLC:
 
 
 
 
 
 
 
 (1) We determined Illudin derivatives are appropriate candidates to develop as novel anticancer agents for NSCLC based on their histiospecificity towards these tumors (and other carcinomas). 
 
 (2) We developed a semi-synthetic class of illudin analogs, Acylfulvenes, with improved in vivo efficacy against NSCLC, including drug-resistant types of NSCLC. 
 
 (3) We developed a metastatic NSCLC xenograft model to aid in screening agents for activity.
 
 (4) We used this screening model to identify a lead candidate known as HMAF (MGI-114) for phase I 
 
 human trials through a combination of in vitro and xenograft studies. 
 
 (5) We obtained external sponsorship, using this data, for phase I human trials of our lead agent HMAF, which are currently completed. Based on promising results from this initial phase I trial, the NCI has 11 phase II trials in progress at various NCI designated Cancer Centers throughout the country and there are 3 additional II trials under commercial sponsorship. In addition, there is currently in progress 3 additional phase I trials designed to determine optimal scheduling, efficacy in pediatric patients, and synergistic potential with Topoisomerase I agents.
 
 
 
 
 
 Despite the marked success of our project there currently remains considerable work to complete. We need to accomplish the following:
 
 
 
 
 
 (1) Identify a promising “backup” or additional Acylfulvene agent for phase I human trials from 100+ we have synthesized to date.
 
 (2) Characterize the initial finding of synergy (increased anticancer activity without additional toxicity) between HMAF and other chemotherapeutic agents.
 
 (3) Identify how HMAF actually works inside the body by determining what occurs to the agent once it has been administered.
 
 
 
 
 
 
 
 Overall, these TRDRP sponsored studies will identify an additional drug for testing in human phase I trials, assist in synthesizing and developing new drugs with increased therapeutic efficacy, guide advanced synergistic trials in humans of HMAF in combination with other anticancer agents, and identify potential mechanisms of action by which the Acylfulvenes function.