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Studies of novel antitumor agents for lung cancers

Institution: University of California, San Diego
Investigator(s): Michael Kelner, M.D., M.S.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0002 Award: $306,000
Subject Area: Cancer
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Due to the prevalence 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 effectiveness. In part, this is because many patients with NSCLC have metastasis (tumor has spread to other sites in the body) and often have recurring cancer after the initial treatment.

Illudins are natural products with a novel chemical structure isolated from the toxic Jack O' Lantern 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 3 years, with support from the TRDRP, we accomplished the following in developing a novel chemotherapeutic agent for NSCLC:

(1) We determined that Illudin-like compounds are appropriate candidates to develop as new anti-cancer agents for NSCLC, based on their specificity for these tumors. (2) We developed a class of Illudin-like compounds, Acylfulvenes, with improved effectiveness against NSCLC, including those resistant to other drugs. (3) We developed a screening system to identify active agents. (4) We used this screening system to identify our lead drug candidate, HMAF (MGI-114). (5) We obtained sponsorship, using these data, for human trials of our lead agent HMAF which are currently in progress. In addition, based on promising results from the initial human trial, the National Cancer Institute has agreed to sponsor up to 11 follow-up trials at various Cancer Centers throughout the United States.

Despite the marked success of our project, there currently remains considerable work to complete. We need to accomplish the following:

• Identify a promising “back up” or additional Acylfulvene drug for human testing from over 100 we have made to date. • Find out why there is increased anticancer activity without additional toxicity when HMAF is given with other chemotherpeutic agents. • Indetify how HMAF actually works inside the body by determining what occurs to the drug once it has been administered.

Overall, these TRDRP sponsored studies will identify an additional drug for testing in humans, assist in developing new drugs with increased effectiveness, guide advanced trials in humans of HMAF in combination with other anticancer agents, and identify how the Acylfulvenes act in the body.

Final Report
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 that 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.

(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 Irofulven (HMAF or 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 Irofulven, which was completed. Based on promising results from this initial phase I trial, several NCI and commercially sponsored phase II trials are in progress at various NCI designated Cancer Centers throughout the country. Additional phase I trials designed to determine optimal scheduling, efficacy in pediatric patients, and synergistic potential with Topoisomerase I agents are in progress. A phase III (final) trial is scheduled to start in the fall of 2000.

In summary, these TRDRP sponsored studies identified a new class of anticancer agents active against cancers resistant to conventional therapy, one of which (Irofulven) is now in final or phase III human trials in an effort to obtain FDA approval.
Publications

Metabolism of antitumor Acylfulvene by rat liver cytosol
Periodical: Biochemical Pharmacology Index Medicus:
Authors: McMorris TC, Elayadi AN, Yu J, Kelner MJ ART
Yr: 1999 Vol: 57 Nbr: Abs: Pg: 83-88

Characterization of MGI 114 (HMAF): Histiospecific toxicity in human tumor cell lines
Periodical: Cancer Chemotherapy and Pharmacology Index Medicus:
Authors: Kelner MJ, McMorris TC, Montoya MA, et al ART
Yr: 1999 Vol: Nbr: Abs: Pg:

Metabolism of antitumor MGI 114 (HMAF) rat liver cytosol
Periodical: Drug Metabolism and Disposition Index Medicus:
Authors: McMorris TC, Elayadi AN, Yu J, Hu Y, Kelner MJ ART
Yr: 1999 Vol: Nbr: Abs: Pg:

Efficacy of MGI 114 against the MRP-positive MV 522 lung carcinoma xenograft
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Kelner MJ, McMorris TC, Estes LA, Oval MY, Rojas RJ, Samson KM ABS
Yr: 1999 Vol: Nbr: 1992 Abs: Pg: 300

Efficacy of MGIII 114 against the MRP-positive metastatic MV522 lung carcinoma xenograft
Periodical: Anti-cancer Drugs Index Medicus:
Authors: Kelner, MJ, McMorris TC, Estes MY, et al ART
Yr: 2000 Vol: 11 Nbr: Abs: Pg: 217-224

Anti-leukemic action of the novel agent MGI 114 HMAF and synergistic action with Topotecan
Periodical: Leukemia Index Medicus:
Authors: Kelner MJ, McMorris TC, Estes KM, et al ART
Yr: 2000 Vol: 14 Nbr: Abs: Pg: 136-141