Editor's Note: Science Scan is a roundup of recently published, biotechnology-relevant research.
Prostate cancer is the most prevalent malignancy in American males. It represents their second-leading cause of cancer death. Localized prostate cancer disease is generally treated with surgery or radiation, and recurrent disease can be temporarily delayed with hormone therapy. However, almost all prostate carcinomas are androgen dependent and fatal. Because of the significant mortality and morbidity associated with prostate disease progression, there is an urgent need for new and targeted treatments.
A recent issue of the Proceedings of the National Academy of Sciences (PNAS) purports to address that need in an article dated Oct. 28, 2003. Its title: "The homodimer of prostate-specific membrane antigen [PSMA] is a functional target for cancer therapy." Its dozen co-authors are at Progenics Pharmaceuticals Inc. and its associated PSMA Development Co., both in Tarrytown, N.Y., in a joint venture between Progenics and Cytogen Corp., of Princeton, N.J. The paper's senior author is William Olson, Progenics' vice president of research and development.
The PNAS paper opens by noting that "prostate-specific membrane antigen is a Type 2 integral membrane glycoprotein. It serves as an attractive target for cancer immunotherapy by virtue of its abundant and restricted expression on the surface of prostate carcinomas."
"Here we report that PSMA is expressed on tumor cells as a noncovalent homodimer," Olson told BioWorld Today. "A truncated PSMA protein lacking transmembrane and cytoplasmic domains also formed homodimers. When used to immunize animals, dimer but not monomer elicited antibodies that efficiently recognized PSMA-expressing tumor cells.
"The PNAS article," Olsen commented, "demonstrates how scientific discoveries on PSMA structure and function can translate into potential therapies for prostate cancer. In further preclinical studies," he added, "our lead PSMA antibody was shown to bind human prostate cancer cells and target their destruction by activating natural immune system functions, including antibody-dependent cellular cytotoxicity (ADCC).
"This ADCC," Olson continued, "is a process whereby certain antibodies can trigger specific components of the body's immune system to kill targeted cells, rather than relying on a cytotoxin or radioisotope that has been attached to the antibody. PSMA is a cell-surface protein expressed on prostate cancer cells at all stages of disease, including metastases," he pointed out. "The PSMA gene was first discovered by scientists at Memorial Sloan-Kettering Cancer Center. It is exclusively licensed to Cytogen Corp., which has sublicensed it to the PSMA Development Co. for in vivo immunotherapy. PSMA also is present at high levels on newly formed blood vessels [neovasculature] needed for the growth and survival of solid tumors. If PSMA-targeted therapies can destroy or prevent formation of new blood vessels, the treatments might prove valuable in a broad range of cancers."
Genetic Locus Linked To Colorectal Cancer, Rare Mutations Accounting For 5 Percent Of Cases
Cancer of the colon is the second-leading cause of malignant mortality among adult Americans. Rare gene mutations that cause definable syndromes account for about 5 percent of all colon cancer cases. Two autosomal, dominant hereditary forms of the disease, familial adenomatous polyposis, hereditary nonpolyposis and hereditary nonpolyposis colorectal cancer, together account for perhaps that 5 percent. However, an additional 20 percent of affected individuals report a family history of the disease in a first-degree relative.
To determine whether these familial groupings reflect a hereditary proneness to colon cancer, or if the susceptibility arises by chance, oncologist Sanford Markowitz at Case Western Reserve University in Cleveland genotyped 53 families in which two or more siblings developed colorectal cancer or large colon adenomas (precursors to the disease) before age 65. They found that affected individuals were more likely to have inherited a specific stretch of DNA on chromosome 9 from their parents, compared to unaffected persons. "These data suggest," Markowitz observed, "that a single locus can contribute to disease susceptibility in a subset of patients with nonsyndromic forms of familial colorectal neoplasia."
The responsible genes have not yet been identified, but at least three candidates lie within the region. Future studies will examine whether that linkage applies to the population at large and will search for the disease-causing genes. Markowitz is senior author of a paper in the Proceedings of the National Academy of Sciences (PNAS) released online Oct. 13, 2003. It's titled: "A subset of familial colorectal neoplasia kindreds linked to chromosome 9q22 [long arm]."
Colorectal cancers themselves develop from precursor colon adenomas. Thus they inherit familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer together. It's marked by hundreds of colon adenomas that then confer a near-100 percent of colon cancer development by the average age of 40.
A subtler adenoma and cancer phenotype is associated with an adenomatous polyposis coli polymorphism in the Ashkenazi Jewish population. The existence of additional disease genes associated with increased risk of colon adenoma and cancer is suggested by observation of a threefold increased risk of colon cancer among first-degree relatives of individuals who develop colon adenomas before age 60.
Therapeutic Cloning Of Embryonic Stem Cells Treats Brain Disorder In Parkinsonian Mice
In the first example for treating a brain disorder, Sloan-Kettering researchers have used dopamine neurons derived from cloned mice embryonic stem cells to treat animal models with a Parkinsonian condition. A loss of dopamine neurons is a hallmark of Parkinson's disease. An article in Nature Biotechnology for October 2003 reports: "Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice."
The goal of therapeutic cloning is to produce specialized cells needed to repair a failing organ from human embryonic stem cells (ESCs) generated by cloning the patient's own cells. Unlike generic ESCs, such cells and their specialized progeny would be genetically identical to the patient and could be transplanted without being rejected by the person's immune system.