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Isolation of lung tumor proteins for a novel treatment

Institution: University of California, San Diego
Investigator(s): Michael Kelner, M.D., M.S.
Award Cycle: 1998 (Cycle 7) Grant #: 7IT-0001 Award: $75,000
Subject Area: Cancer
Award Type: Inno Dev & Exp Awards (IDEAS)
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 developed a class of Illudin-like compounds, Acylfulvenes, with improved effectiveness against NSCLC, including those resistant to other drugs. (2) We used a screening model to identify a lead candidate known as HMAF (MGI-114) for initial trials in humans. (3) 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 identify the nature of the proteins located on the surface of lung tumor cells which permit the rapid entry of Illudins into these cancer cells. Identification of these lung cancer proteins will allow the use of advanced techniques of drug design, such as computer modeling, to design Illudin-like compounds with improved anticancer activity. Basic knowledge about expression of these proteins in lung cancer will also provide insight into how and why these cancers develop.
Publications

Identification of proteins binding to acylfulvenes.
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Kelner MJ, Elayadi A, McMorris TC ABS
Yr: 2000 Vol: 41 Nbr: 656 Abs: Pg:

Phage display panning of irofulven identifies potential intracellular targets.
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Kelner MJ, Tsigelny I, Sharikov V, Ten Eyck LF, Elayadi AN, McMorris TC ABS
Yr: 2001 Vol: Nbr: Abs: Pg: 45

Phage display panning of irofulven identifies potential intracellular targets
Periodical: Clinical Cancer Research Index Medicus:
Authors: Kelner MJ, Tsigelny I, SHarikov V, Ten Eyck LF, Elayadi AN, McMorris TC ABS
Yr: 2001 Vol: 7 Nbr: Abs: 220 Pg: