Will Science Stop Mesotheliomas by Depriving the Tumor Cells of a Needed Ingredient for Growth, at L
How will mesothelioma tumors be treated in a decade ? Will lives be extended for many years? Will every person with mesothelioma seek gene therapy as a remedy ? Will Madison and St. Clair Counties find new cancers to focus on instead ?
The preceding questions are no doubt somewhat fanciful. But, science is pressing ahead. Thus, a Phase 2 clinical trial is now underway in the UK to try to stave off mesotheliomas by depriving the tumors of an amino acid (arginine) that some mesothelioma tumor cells need to grow. The theory is that an enzyme known as ADI-PEG 20 will block production of the arginine, and leave the tumor unable to grow. Set out below is the press release from the sponsor – Polaris Group, a San Diego based entity. The company also intends to try the same tactic against small cell lung cancer (SCLC), which is the basic name for forms of lung cancer almost exclusively tied to cigarette smoking.
Polaris’ website includes a medical literature section, and it includes an abstract from which the following excerpt is drawn, as to a Phase 1 trial of ADI-PEG 20. The numbers are relatively encouraging:
"Results: In keeping with the cell line data, 63% (52 of 82) of patients had tumors displaying reduced or absent AS protein, as assessed using a tissue microarray. Cell viability declined markedly in the AS-negative cell lines 2591and MSTO but not in the AS positive cell line, 28.This response was apparent by day 4 and maintained by day 9 in vitro. Arginine depletion induced BAX conformation change and mitochondrial inner membrane depolarization selectively in AS-negative MPM cells.
Conclusions: In summary, we have identified AS negativity as a frequent event in MPM in vivo, leading to susceptibility to cytotoxicity following restriction of arginine. A phase II clinical trial is planned to evaluate the role of arginine depletion in patients with AS negative MPMding to susceptibility to cytotoxicity following restriction of arginine. A phase II clinical trial is planned to evaluate the role of arginine depletion in patients with AS negative MPM."
Hat tip to Genetic Engineering & Biotechnology News.
The Polaris press release is below.
Date: March 18, 2011
Polaris Enrolls First Patient in Phase 2 Clinical Trial of ADI-PEG 20 for the Treatment of Malignant Mesothelioma
Enzyme-Based Cancer Therapy Now Being Evaluated in Multiple Cancers
SAN DIEGO, March 18, 2011 — Polaris Group announced today the enrollment of the first patient in a Phase 2 clinical trial of ADI-PEG 20 (pegylated arginine deiminase), the company’s novel enzyme-based treatment for malignant mesothelioma. This randomized trial, called "ADAM" (Arginine Deiminase And Mesothelioma), will evaluate the treatment efficacy of ADI-PEG 20 as a single agent compared to the best supportive care. The primary endpoint of the study is progression free survival.
Peter Szlosarek, M.D., Ph.D., of the Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, is the lead investigator of the study. "It is with great anticipation that the ADAM trial has opened at Barts and other cancer centers in the U.K., including hospitals in Belfast, Cambridge, Hull, Manchester and Southampton." said Dr. Szlosarek. "We are pleased to be joining Polaris Group in exploring the potential benefits of ADI-PEG 20 in treatment of different cancers."
Malignant mesothelioma is a cancer of the lungs that frequently occurs in people who have been exposed to asbestos. The disease is usually diagnosed two to three decades after prolonged exposure and when it has generally spread beyond the stage for successful surgical treatment. The prognosis for patients with late stage malignant mesothelioma is poor with a median survival of less than one year.
Polaris Group scientists and colleagues have been investigating the metabolic enzyme argininosuccinate synthetase (ASS) and its presence or absence in relationship to growth of normal cells and tumor cells. ASS is required for the production of arginine, an amino acid needed for growth and replication of cells. Normal cells have normal levels of ASS and can produce sufficient arginine for their own growth and survival. However, many types of tumor cells cannot make their own arginine due to a deficiency in ASS and, therefore, must obtain it from external sources. ADI-PEG 20 depletes the external supply of arginine, causing these tumor cells to die.
The sensitivity of several ASS-deficient tumor cell lines to ADI-PEG 20 has been recently reported at the 2010 Annual Meeting of the American Association for Cancer Research. Previous studies supported by Cancer Research UK (CR-UK) and conducted by Dr. Szlosarek demonstrated that 63 percent of patients with malignant mesothelioma had low levels or no ASS in their tumor tissues. The study also demonstrated that viability of mesothelioma cell lines from these patients declined markedly when deprived of arginine if they were ASS-negative.
Robert Jackson, Ph.D., chairman of the CR-UK Discovery Committee, and a member of the Polaris Scientific Advisory Board, commented: "We are very excited to have started the study with ADI-PEG 20 in malignant mesothelioma. Dr. Szlosarek has been one of the leaders in researching and targeting ASS-deficient tumors with ADI-PEG 20. The initiation of this mesothelioma trial with ADI-PEG 20 is a good example of a CR-UK funded laboratory study forming the basis of a new experimental treatment. CR-UK is committed to such important translational research initiatives in cancer."
John Bomalaski, M.D., executive vice president, medical affairs, of Polaris Group, added, "We are very excited about the potential of using ADI-PEG 20 to treat multiple forms of cancer. We are already evaluating ADI-PEG 20 in a Phase 2 trial in small cell lung cancer, and we look forward to initiating additional trials in tumors with a high degree of ASS deficiency. Our belief is that ADI-PEG 20 will play a key role in the future as single agent therapy or in combination chemotherapy for several cancers that continue to evade effective treatment."