The Rapid Reporter: June 2007

By John D. Zoidis, MD and Diane West
Published: Wednesday, Jul 14, 2010

    April 14-18, 2007

    Los Angeles, CA

    Reports by John D. Zoidis, MD

New Research in Malignant Mesothelioma

Novel Biomarkers May Make Early Detection in High-Risk Patients Possible, and Onconase May Have Potential as a Chemopreventive Agent

Ranpirnase (Onconase®) may have potential as a chemopreventive agent, according to world-renowned malignant mesothelioma (MM) researcher Michele Carbone, MD, PhD, Professor and Director of the Thoracic Oncology Program and Clinical Professor of Pathology at the University of Hawaii’s Cancer Research Center of Hawaii and Chairman of the Alfacell Thoracic Advisory Board, who moderated a series of poster presentations at the annual meeting of the American Association for Cancer Research, Los Angeles, CA, April 14-18, 2007.

Dr. Carbone highlighted the growing worldwide problem of asbestos exposure and its link to MM. He presented data showing that early detection in patients at high risk for developing MM is becoming more prevalent as a result of recently recognized biological markers, including soluble mesothelin-related protein (SMRP) and osteopontin (OPN).

Dr. Carbone and his team of investigators evaluates whether these novel biomarkers could identify MM in its early stages in high-risk persons in Cappadocia, Turkey, where 50% of all deaths are caused by MM. Fresh sera were collected from 69 healthy persons ≥30 years of age, at 3 month intervals, and compared to sera from 11 individuals with a confirmed diagnosis of MM. A separate cohort of 12-year-old frozen sera from 72 apparently healthy villagers and 8 with known MM were also analyzed. Excellent discrimination for SMRP and OPN between healthy and MM was seen. For the 12-year-old sera, the SMRP and OPN sensitivity and specificity were preserved. The investigators concluded that SMRP and OPN are ex¬traordinarily promising markers for identifying early-stage MM in high-risk cohorts.

Dr. Carbone also discussed the favorable toxicity profile and well-documented mechanism of action of Onconase, which directly affects the ubiquitin-proteasome proteolytic (UPP) pathway—the biomolecular pathway that has been shown to cause asbestos-related carcinogenesis. The elucidation of this pathway and future clinical testing may lead to the use of Onconase as a chemopreventive agent to potentially prevent the onset of MM, or reduce the doses of cytotoxic agents needed in patients who develop the disease.

According to Dr. Carbone, “The potential of Onconase as an early, first-line preventative treatment for mesothelioma is an exciting development that we plan to investigate through clinical trials. With approximately more than 25 million asbestos exposure cases reported worldwide, we believe that Onconase might play a greater role in the treatment protocols for a much larger population than was originally envisioned for this dismal disease.”

Onconase is a therapeutic product candidate based on Alfacell’s proprietary ribonuclease (RNase) technology. Onconase is a natural protein isolated from the leopard frog, and has been shown in preclinical models to target cancer cells while sparing normal cells. Onconase triggers apoptosis, the natural death of cells, via multiple molecular mechanisms of action.

Bavituximab Equivalent Generates Curative Immune Responses as Part of a Vaccine-Like Regimen in Preclinical Models of Aggressive Glioma

The results of preclinical studies evaluating the antitumor responses to 2aG4—a mouse equivalent to the Peregrine Pharmaceuticals’ antiphosphatidylserine (anti-PS) antibody bavituximab—were presented at the annual meeting of the American Association for Cancer Research, Los Angeles, CA.

Anionic phospholipids, primarily PS, become exposed on the external surface of vascular endothelial cells in tumors, providing an excellent marker for tumor vascular targeting. Dr. Jin He and colleagues at the University of Texas Southwestern Medical Center, Dallas, TX explored the possibility of enhancing the immunogenicity of irradiated glioma cells by treating them with 2aG4 in vitro.

In previous research, Dr. He and colleagues treated rats with orthotopic glioblastoma with single-fractionated radiation combined with 2aG4. The treatment resulted in a marked prolongation of survival time and some tumor cures (15%). Surviving animals were immune to intracerebral challenge with live, untreated F98 glioma cells. These findings suggested that PS on tumor cells might be suppressing the host immune response to the tumor cells and that blocking PS with 2aG4 restored immunogenicity.

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