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Studies of novel antitumor agents for lung carcinoma

Institution: University of California, San Diego
Investigator(s): Michael Kelner, M.D., M.S.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0057 Award: $833,491
Subject Area: Cancer
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
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.
Publications

Activity of Irofulven (MGI 114, HMAF) in combination with other chemotherapeutic agents
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Kelner MJ, McMorris TC ABS
Yr: 2001 Vol: 42 Nbr: 476 Abs: Pg: 88

Structure-activity studies of antitumor agent irofulven (hydroxymethylacylfulvene) and related analogues.
Periodical: Journal of Organics Chemistry Index Medicus:
Authors: McMorris TC, Yu J, Lira R, Dawe R, MacDonald JR, and Kelner MJ ART
Yr: 2001 Vol: 6 Nbr: Abs: Pg: 6158 - 6163

Enhanced antitumor activity of irofulven in combination with thiotepa or mitomycin C.
Periodical: Cancer Chemotherapy and Pharmacology Index Medicus:
Authors: Kelner MJ, McMorris TC, Rojas RJ, Trani NA and Estes I ART
Yr: 2002 Vol: 49 Nbr: Abs: Pg: 412-418

Phage display panning of irofulven identifies potential intracellular targets.
Periodical: Clinical Cancer Research Index Medicus:
Authors: Kelner MJ, Tsigelny I, Sharikov V, et al ABS
Yr: 2001 Vol: 7 Nbr: Abs: 220 Pg:

Irofulven is synergistic with multiple chemotherapeutic agents.
Periodical: American Association for Cancer Research Index Medicus:
Authors: Kelner MJ, and McMorris TC ABS
Yr: 2002 Vol: 43 Nbr: 60 Abs: 304 Pg:

Anti-leukemic action of the novel agent MGI 114 (HMAF) and synergistic action with Topotecan.
Periodical: Leukemia Index Medicus:
Authors: Kelner M, McMorris TC, Estes L, Samson KM, Trani NA, MacDonald JR ART
Yr: 2000 Vol: 14 Nbr: Abs: Pg: 136-141

Efficacy of MGI 114 against the MRP-positive metastatic MV522 lung carcinoma xenograft.
Periodical: Anti-cancer Drugs Index Medicus:
Authors: Kelner MJ, McMorris TC, Estes LA, Oval MY, Rojas RJ, Lynn JR, Lanham KA, Samson KM. ART
Yr: 2000 Vol: 11 Nbr: Abs: Pg: 217-224

Preparation and biological activity of amino acid and peptide conjugates of antitumor hyroxylmethylacylfulvene.
Periodical: Journal of Medicinal Chemistry Index Medicus:
Authors: McMorris TC, Yu J, Ngo HT, Wang H, Kelner MJ ART
Yr: 2000 Vol: 43 Nbr: Abs: Pg: 3577-3580

Sequiterpenes from the basidiomycete omphalotus illudens.
Periodical: Journal of Natural Products Index Medicus:
Authors: McMorris TC, Lira R, Gantzel PK, Kelner MJ, Dawe R ART
Yr: 2000 Vol: 63 Nbr: Abs: Pg: 1557-1559

Structure-activity studies of antitumor agent irofulven (HMAF) and related analogues.
Periodical: Journal of Organics Chemistry Index Medicus:
Authors: McMorris TC, Yu J, Lira R, Dawe R, MacDonald JR, Kelner MJ ART
Yr: 2001 Vol: 6 Nbr: Abs: Pg: 6158-6163

Enhanced antitumor activity of irofulven in combination with antimitotics.
Periodical: Investigational New Drugs Index Medicus:
Authors: Kelner MJ, McMorris TC, Rojas RJ, Trani NA, Estes L ART
Yr: 2002 Vol: 20 Nbr: Abs: Pg: 267-279

Sesquiterpenes from omphalotus illudens
Periodical: Phytochemistry Index Medicus:
Authors: McMorris, Kashinatham A, Lira R, Rundgren H, Gantzel PK, Kelner MJ, Dawes R ART
Yr: 2002 Vol: 61 Nbr: Abs: Pg: 395-398

Genotoxic action of anti-tumor illudin compounds including irufulven.
Periodical: DNA Repair Index Medicus:
Authors: Jaspers NGJ, Raams A, Kelner MJ, Ng J, Takeda S, McMorris, Hoeijmakers JHJ ART
Yr: 2002 Vol: 11 Nbr: Abs: Pg: 1027-1038

Reaction of irofulven with zinc and acid
Periodical: Journal of Natural Products Index Medicus:
Authors: McMorris TC, Moon S, Kelner MJ ART
Yr: 2003 Vol: 66 Nbr: Abs: Pg: 310-312

Structure-activity relationship studies of illudins: Analogs possessing a spiro-cyclobutane ring.
Periodical: Journal of Organics Chemistry Index Medicus:
Authors: McMorris TC, Cong Q, Kelner MJ ABS
Yr: 2003 Vol: 68 Nbr: Abs: Pg: 9648-9653