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Bispecific molecular therapy of small cell lung cancer

Institution: University of California, San Diego
Investigator(s): Edward Ball, M.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10RT-0064 Award: $434,805
Subject Area: Cancer
Award Type: Research Project Awards

Initial Award Abstract
Long-term survival for patients with small cell lung cancer (SCLC) is rare. Even when the initial response to chemotherapy treatment is good, the majority of the patients develop resistance to chemotherapy and the cancer grows back, usually within one year. This research proposal is aimed at developing new ways to treat this cancer by harnessing the immune system and by taking advantage of an important feature of SCLC cells that provides a new target for therapy. SCLC cells produce bombesin (BN)-like peptides, which are a type of hormone known as neuropeptides. These peptides promote growth of the cancerous cells. SCLC is the first human tumor identified to produce BN-like peptides and process receptors for BN-like peptides on the cell surfaces. High levels of these receptors have been found in the majority of SCLC cell lines, as well as in SCLC patient tumor tissues. Recent studies show that growth of SCLC cells in the test tube as well as in patients was inhibited by an antibody against BN peptide.

We have developed a new therapeutic agent to treat SCLC that takes advantage of the fact that SCLC cells display the receptors for BN-like peptides on their surfaces. Our new agent combines the short peptide sequence of BN with a humanized monoclonal antibody, one of the newest and most exciting developments in cancer therapy. We call this agent a bispecific molecule (BsMol). The monoclonal antibody is designed to direct normal white blood cells to kill the cancer cells that the BsMol binds to through the BN short peptide. We have shown that this BsMol binds to SCLC cells in vitro, and causes destruction of the tumor cells. A U.S. patent [#5833985] was awarded to the Principal Investigator for the invention of this novel molecular therapy for cancer.

In this study, we will improve the construction of the BsMol, study the optimal conditions for such a BsMol to cause tumor cell killing, and investigate how the agent causes the destruction of established SCLC tumors in a mouse model. We also will study the combined effect of this agent with standard chemotherapy drugs on the SCLC tumor cells. Results from this mouse model should be applicable to human lung cancer because these molecules have been shown to function identically in mice and in humans; therefore, these studies will allow the rational design of clinical trials for patients with SCLC.

Growth inhibition of small cell lung cancer (SCLC) cell lines mediated by IFN-y activated human monocytes and H22xBN-antagonish in combination with paclitaxel.
Periodical: American Association for Cancer Research Index Medicus:
Authors: Zhou JH, Chen J, Mokotoff M, and Ball ED ABS
Yr: 2002 Vol: 43 Nbr: Abs: Pg: 255

Bombesin/gastrin-releasing peptide receptor: a potential target for antibody-mediated therapy of small cell lung cancer.
Periodical: Clinical Cancer Research Index Medicus:
Authors: Zhou JH, Chen J, Mokotoff M, Zhong RK, Shultz LD, Ball ED ART
Yr: 2003 Vol: 9 Nbr: Abs: Pg: 4953-4960

A bispecific molecule, H22xAntag 2, in combiniation with chemotherapy increases the killing of small cell lung cancer (SCLC) cells in the presence of cytokine-activated monocytes and macrophages.
Periodical: American Association for Cancer Research Index Medicus:
Authors: Zhou JH, Chen J, Mokotoff M, Ball ED ABS
Yr: 0 Vol: Nbr: Abs: Pg:

Caution in the use of 2-iminothiolane (traut's reagent) as a cross-linking agent for peptides. The formation of N-peptidyl-2-iminothiolanes with bombesin (BN) antagonist (D-Trp, Leu 13-psi)
Periodical: Journal of Peptide Research Index Medicus:
Authors: Mokotoff M, Mocarski YM, Gentsch BL, Miller M, Zhou J-H, Chen J, Ball ED ART
Yr: 2001 Vol: 57 Nbr: 5 Abs: Pg: 383-389

Targeting gastrin-releasing peptide receptors for cancer treatment.
Periodical: Anti-cancer Drugs Index Medicus:
Authors: Zhou J-H, Jian Chen J, Mokotoff M, Ball ED ART
Yr: 2004 Vol: 15 Nbr: Abs: Pg: 921-927