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Posted by: cjgaddy Member Level  Date: Saturday, July 30, 2005 8:23:28 PM
In reply to: None Post # of 55981  Send a link via email Share on Facebook Tweet this post
Tarvacin+Docetaxel: Susan G. Komen Grant

Recall this paragraph in the 5-16-05 PR announcing a CANCER RESEARCH (AACR) article “Data Published in Cancer Research Shows That Tarvacin Plus Docetaxel Inhibits Breast Tumor Growth by 93% - Combination Therapy Also Inhibits Tumor Colonies in the Lung by 93% Without Added Toxicity”:

“Dr. Huang is an assistant professor of pharmacology in Dr. Philip Thorpe's laboratory at the UT-SW Medical Ctr. at Dallas. Further pre-clinical studies studying the potential of Tarvacin in the treatment of drug-resistant breast cancer and in breast cancer metastasis are ongoing at UT Southwestern under a grant by the Susan G. Komen Breast Cancer Foundation and a sponsored research agreement with Peregrine Pharmaceuticals.
http://ir.peregrineinc.com/phoenix.zhtml?c=74236&p=irol-newsArticle&ID=710185

Well, that grant has been posted to the Komen Foundation website, along with the abstract of the grant. We now know it was for $247k. Pay particular note to this in the abstract, “Since 3G4 is already chimerized and close to clinical trials, it should be possible to take the 3G4/Docetaxel combination rapidly into clinical trials in breast cancer patients.”

So, do we expect a separate “Tarvacin+Docetaxel Combo” IND at some point, or is Tarvy+Doce going to be an “extension protocol” offered in the current A.C.C. ALL-SOLID-CANCERS trial: “Patients who demonstrate an objective response may be offered continued treatment on an extension protocol." ? ? ?

Susan G. Komen Breast Cancer Foundation
2004-2005 Grant Cycle - Research Grants Awarded
Posted: June 24, 2005 Grant Class: Biology of Breast Cancer
Grant for $247,318
Grant Name: “Novel Vascular Targeting Antibody, 3G4, Enhances the Therapeutic Efficacy of Docetaxel Against Drug Resistant Breast Cancer and Metastases”
Xianming Huang, PhD [member of Dr. Thorpe’s Lab]
UT Southwestern Medical Center at Dallas
http://www.komen.org/grants/awards/abstracts.asp?EM=378923.988627/2/200437894.800816&ID=6&no...

Scientific Abstract:
Background: A therapeutic monoclonal antibody, 3G4, directed against tumor vasculature was generated in this laboratory. A chimeric version is scheduled to enter Phase I clinical trials in late 2004. The antibody recognizes phosphatidylserine (PS), a specific marker of tumor vessels. When injected into tumor-bearing mice, 3G4 localizes specifically to tumor blood vessels, induces damage to tumor vessels and suppresses tumor growth in multiple tumor types. When combined with Docetaxel, results were even more remarkable. In an orthotopic human breast tumor model in mice, the combination of 3G4 and Docetaxel inhibited tumor growth by 93%, as compared with 60% and 68%, decreased tumor burden in the liver and lungs by more than 90%, as compared with 45% and 56%, for 3G4 and Docetaxel alone, respectively. Importantly, the combination is no more toxic than is Docetaxel alone.
Objective/Hypothesis: We hypothesize that combining 3G4 with Docetaxel will have high efficacy in the treatment of primary human breast tumors and their metastases. Also, since 3G4 targets the stable tumor endothelium rather than tumor cells themselves, we hypothesize that the therapy will be effective against drug resistant breast tumors.
Specific Aims: 1) To assess the efficacy and safety of the combination of 3G4 and Docetaxel against MDA-MB-435, T0.1 taxol-resistant human breast tumor and 4T1 syngeneic mouse mammary tumor. 2) To assess the anti-metastatic effect of the combination. 3) To dissect the mechanisms of the antitumor effect. Study Design: Optimal dosing schedules will be determined in mice bearing orthotopic breast tumors and taxol-resistant variants. The spontaneous metastatic model will be established using a luciferase labeled MDA-MB-435-luc cell line. Experimental metastatic models will be setup by iv injection of breast tumor cells. To dissect the mechanisms, vascular damage will be assessed by measuring microvessel density and functional vascular volume in tumors. Metastases will be assessed by non-invasive imaging and quantified by luciferase assay.
Potential Outcomes and Benefits of the Research: The proposed studies could ultimately lead to the development of a new and more effective strategy for the treatment of human breast tumors. Since 3G4 is already chimerized and close to clinical trials, it should be possible to take the 3G4/Docetaxel combination rapidly into clinical trials in breast cancer patients.

Lay Abstract:
“A novel vascular targeting antibody, 3G4, enhances the therapeutic efficacy of Docetaxel against drug resistant breast cancer and metastases Antiangiogenic agents that attack tumor blood vessels and starve tumors of oxygen and nutrients have shown promising clinical activity, especially when combined with chemotherapeutic drugs. The goal of the present study is to explore our finding that a novel vascular targeting antibody, 3G4, markedly improves the therapeutic efficacy of Docetaxel, a key drug for treating breast cancer. The target for 3G4 is phosphatidylserine (PS), a recently identified specific marker of tumor vasculature. We found that 3G4, as a single agent, suppresses tumor growth by 60% to 75% in two different human breast tumor models in mice. When combined with Docetaxel, results were even more remarkable. In a human breast tumor model in mice, 3G4 plus Docetaxel inhibited tumor growth by 93%, as compared with 60% and 68% for 3G4 and Docetaxel, respectively. The combination therapy decreased tumor burden in the liver and lungs by more than 90%, as compared with 45% and 56% decrease for 3G4 and Docetaxel, respectively. The combination was also effective against drug resistant breast tumors. Importantly, the combination is no more toxic to mice than is Docetaxel alone. The hypothesis underlying the proposed studies is that combining 3G4 with Docetaxel will lead to significantly enhanced therapeutic effects for the treatment of human breast tumors. We propose to examine the antitumor effect in three different breast tumor models, including drug resistant breast tumors, each represents different clinical settings of human breast cancer. We will then evaluate the efficacy of the combined therapy on tumor metastasis. Finally, we will attempt to clarify the mechanism. A human-mouse chimeric version of 3G4, which has similar preclinical activities to murine 3G4, has been made in gram-quantities by a pharmaceutical company and is scheduled to enter Phase I clinical trials in cancer patients at the end of 2004. The chimeric 3G4 is safe in monkeys, atherosclerotic rabbits and rodents even at dose 10-fold higher than the calculated therapeutic dose. The proposed studies could ultimately lead to the development a new and more effective strategy for the treatment of human breast tumors. Since 3G4 is already chimerized and close to clinical trials, it should be possible to take the 3G4/Docetaxel combination rapidly into clinical trials in breast cancer patients.”

www.komen.org
“For 18 years, the Susan G. Komen Breast Cancer Foundation has provided funding for basic, clinical and translational breast cancer research and for innovative projects in the areas of breast health education and breast cancer screening and treatment. In addition, the Foundation awards three-year postdoctoral fellowships to individuals working under the guidance of experienced cancer researchers in order to recruit and retain young scientists in the field of breast cancer research. Credited as a leading catalyst in the fight against breast cancer, the Komen Foundation runs one of the most innovative, responsive grant programs in breast cancer research today with a focus on research projects with potential for high impact that may not be considered by other agencies.”

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5-15-05 UT-SW PR: Thorpe/Huang 3G4/Breast CANCER RES. Article

Latest News from UT Southwestern – May 15, 2005
http://www.utsouthwestern.edu/utsw/cda/dept37389/files/223516.html
“Antibody combined with cancer drug shows promise against breast tumors”
DALLAS, May 15 2005: An antibody that targets the blood vessels nourishing tumors significantly reduced breast cancer formation and growth in mice when combined with a current cancer drug, according to researchers at UT Southwestern Medical Center.

Their work appears in today's issue [5-15-05] of Cancer Research.

"This antibody could enhance the therapeutic efficacy of the drug Docetaxel in breast cancer patients," said Dr. Philip Thorpe, professor of pharmacology at UT Southwestern and senior author of the research. "The combination merits further scrutiny as a potential treatment for human cancer."

PICTURE OF THORPE IN LAB:
“Dr. Philip Thorpe, professor of pharmacology, and other UT Southwestern researchers, have shown that an antibody that targets blood vessels nourishing tumors significantly reduced breast cancer formation and growth in mice when combined with a current cancer drug.”
http://www.utsouthwestern.edu/findfac/professional/0,2356,17308,00.html

Docetaxel is one of the most effective chemotherapeutic drugs for treating breast, ovarian and prostate cancer, but its use in treating other cancers is limited by its toxicity.

In their study of mice, Drs. Thorpe and Xianming HUANG, assistant professor of pharmacology in the Harold C. Simmons Comprehensive Cancer Center, found the antibody compound 3G4 was effective as a vascular targeting agent ( VTA ) when used with Docetaxel. VTAs are designed to find and destroy blood vessels within cancerous tumors, cutting off their blood supply.

Specifically, mice with human breast tumors treated with 3G4 and Docetaxel had a 93% reduction in overall tumor growth. The injected breast cancer cells also stimulated the growth of tumor colonies in the lungs, and the drug combination reduced the average number of those colonies by 93%, with half of the mice not developing any lung tumors.

The combination of 3G4 and Docetaxel was much better than either compound used by itself, Dr. Thorpe said. In mice with breast cancer tumors, growth was suppressed by 50% using 3G4 alone and 70% for Docetaxal alone. The reduction in lung tumor colonies was 82% with 3G4 alone and 78% with Docetaxal alone.

Peregrine Pharmaceuticals is developing a version of 3G4 called Tarvacin for cancer treatment and recently received approval from the FDA for a phase I clinical trial. The compound was discovered by Dr. Thorpe's lab, and Peregrine has a sponsored research agreement with UT Southwestern to further develop the drug.

"We are currently investigating whether the enhanced therapeutic efficacy with 3G4 and Docetaxel extends to other tumor models and other conventional therapies," Dr. Thorpe said.

VTAs like 3G4 target tumor vessels by selectively binding to a certain component in the membranes of endothelial cells that line tumor blood vessels. This component, called an anionic phospholipid, faces the interior of cells in normal blood vessels.

In tumor blood vessels, however, changes in the tumor environment cause the phospholipid to flip inside out and be positioned on the external surface. VTAs then can bind to this exposed phospholipid, causing the body's white cells to attack and destroy the vessels feeding the tumor.

By targeting receptors unique to tumor vessels, vascular targeting agents kill tumors without causing damage to surrounding healthy tissue. They also reduce the risk of side effects by operating at lower doses than traditional cancer therapies because they are effective without needing to penetrate the innermost layer of a tumor.

And, while drug resistance caused by the instability and mutability of cancer cells is a significant problem with conventional therapies that target tumor cells, cells targeted by VTAs do not mutate to become drug resistant, Dr. Thorpe said.

Tarvacin itself has shown promise in mice against cancers in the fibrous tissues, brain cancers and Hodgkin's disease.

Mary Bennett, a UT Southwestern technician, also contributed to the Cancer Research study.

Research was funded by Peregrine Pharmaceuticals, a grant from the Gillson Longenbaugh Foundation and a Specialized Programs of Research Excellence (SPORE) grant in lung cancer research through the National Cancer Institute. Further studies are being funded by the Susan G. Komen Breast Cancer Foundation.

= = = = = = = = = = =
PPHM PR 5-16-05: Can.Res article, TARVACIN+DOCETAXEL INHIBITS BREAST TUMOR GROWTH BY 93%

”Data Published in Cancer Research Shows That Tarvacin Equivalent Plus Docetaxel Inhibits Breast Tumor Growth by 93% - Combination Therapy Also Inhibits Tumor Colonies in the Lung by 93% Without Added Toxicity”
http://ir.peregrineinc.com/phoenix.zhtml?c=74236&p=irol-newsArticle&ID=710185
AACR Cancer Research Magazine: http://cancerres.aacrjournals.org


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