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Latest cancer research features small molecule therapy, and the preventative benefits of sunshine

  [ 63 votes ]   [ Discuss This Article ] • March 31, 2004

Small molecules holds key to thyroid tumor treatment and the elusive, ‘undruggable cmyc oncogene; and the sun is good for non-hodgkin lymphoma prevention ORLANDO –

Among the latest breaking cancer research presented today scientists described a small molecule that locks into DNA structures, inhibiting the expression hard-to-target oncogenes. In another application a of small molecule targeted drug therapy, an agonist turns on a gene-regulating pathway to inhibit growth and metastasis in deadly thyroid tumors. From down under, Australian researchers found that sun worshippers are taking steps to prevent non-Hodgkin Lymphomas. This research was presented here at the 95th Annual Meeting of the American Association for Cancer Research.

In vivo cfficacy of CX-3543, a novel c-Myc oncogene inhibitor: Abstract No. LB-243

Cancer researchers today unveiled a new small molecule drug that specifically targets c-Myc, a key growth promoting regulator in cancers and a gene that has escaped all efforts to control it. William Rice, Ph.D., the presenting author on a team of scientists from Cylene Pharmaceuticals, San Diego, Calif., said that the small molecule CX-3543 effectively reduced cMyc mRNA expression by 85 percent in colorectal tumor animal models. The small molecule inhibited growth of prostate and pancreatic tumor models in mice as well. Each of those tumor cell types are known to produce high levels of cMyc during tumor growth. "We have identified a small molecule with drug-like properties that is a candidate for further preclinical development," Rice said. CX-3543 selectively suppresses cMyc activity by specifically binding to the cMyc quadruplex, he said.

G-quadruplex structures are four stranded DNA secondary structures. Certain G-quadruplexes regulate transcription of specific oncogenes, including cMyc. The quadruplex cluster that includes cMyc also includes VEGF, a growth factor that regulates development of blood vessels to tumors. CX-3543 inhibits VEGF expression as well as cMyc. "We selected CX-3543 as the first 'Oncogene Inhibitor' class of small molecule compounds that specifically target the G-quadruplex regulatory elements in the genes involved in growth and proliferation of tumors," Rice said.

Small molecule drugs such as CX-3543 are compelling because they can be targeted to previously "undruggable" genes such as cMyc, Rice said. Furthermore, bioassays are already established to identify the efficacy of the small molecule action on their respective targets, and biomarkers are available to follow drug-induced responses in preclinical and clinical studies.

Sun exposure may protect against non-Hodgkin lymphoma: A case-control study: Abstract LB-228

Those who bask in sunlight increase their risk of developing skin cancer, but sun worshippers may also be protecting their bodies from non-Hodgkin lymphoma, Australian researchers said today. By comparing sunlight exposure among 704 patients with non-Hodgkin lymphoma to 694 healthy individuals, scientists from The University of Sydney determined that people with more lifetime exposure to sunlight reduced their risk of developing Non-Hodgkin lymphoma by as much as 53 percent.

The study, led by Bruce Armstrong, A.M. F.A.A., examined the risk of developing non-Hodgkin lymphoma through total time spent outdoors: time outdoors on days off work and sun exposure during vacations. The analysis indicated an inverse relationship between sunlight exposure and incidence of non-Hodgkin Lymphoma; the more sunlight, the less the risk.

The 25 percent of individuals with the most total sunlight exposure had an odds ratio of 0.65. With less sunlight exposure, the risk increased. Each subsequent quartile had progressively more risk of developing the disease. The 25 percent of trial subjects who experienced the least amount of outdoor time under the sun had an odds ratio of 1.0.

Outdoor time on days off work was most strongly related to reduced risk of non-Hodgkin lymphoma. The upper quartile of "sun worship" had an odds ratio of 0.47--a whopping 53 percent reduction in risk of the disease. High exposure to the sun during vacations also reduced risk cancer risk by 40 percent, to an odds ratio of 0.60

The researchers noted that the effects were stronger in women than men. And the benefit worked the best for those who were outdoors most as children. "The apparent effect of total hours outdoors was greatest with childhood exposure," Armstrong said. Armstrong suggested that the effect may be due, in part, to role of sunshine stimulating production of vitamin D in the skin,

Incidence of Non-Hodgkin lymphoma ranked among the top ten cancers in the Unites States during 2000. More than 18 people per 100,000 U.S. residents developed the disease that year and there were an estimated 314,000 non-Hodgkin Lymphoma patients in the United States. Worldwide, more than 160,000 people die from the disease each year.

A novel high-affinity PPARgamma agonist inhibits human thyroid tumor growth: Abstract No. LB-17

An apparently normal protein receptor found in treacherous anaplastic thyroid tumors may provide the keyhole through which a novel small molecule unlocks molecular pathways leading to tumor cell death, Mayo Clinic and Sankyo Company scientists said today. Anaplastic thyroid tumors make up just one percent of all thyroid cancers, but they are deadly and respond to no current treatment. Patients diagnosed with anaplastic thyroid cancer rarely survive more than a year, with a median survival of 3 months.

These aggressive and fatal tumors differ from other more treatable types of thyroid cancers by virtue of having no rearrangement in Pax8/PPARgamma fusion genes common to a follicular subtype of thyroid tumor. The unaltered peroxisome proliferator-activated receptor gamma (PPARgamma) found in anaplastic thyroid tumors is apparently in tact, providing a way by which RS-5444, a novel drug therapy, can unlock mechanisms leading to reduced tumor mass and control of the cancer, explained John Copland, Ph.D., Mayo Clinic Jacksonville, Florida. Copland said that the small molecule PPARgamma agonist, RS-5444, binds tightly to the cellular receptor in cell lines derived from human anaplastic thyroid tumors, and inhibits growth of those cells in culture.

The treatment is effective in in vivo models as well. "In the nude-mouse animal model injected with the tumor cells, RS-5444 inhibited tumor growth 3-4 fold," Copland said. In studies that combine RS-5444 with other drugs, Copland has noted amplification of the effect of this agonist. Either by itself or more likely in combination with other therapies, RS-5444 may lead to a more effective treatment for this cancer, said Robert Smallridge, M.D., another lead researcher on this project and a Mayo Clinic endocrinologist who specializes in the treatment of thyroid cancer.

Founded in 1907, the American Association for Cancer Research is a professional society of more than 22,000 laboratory, translational, and clinical scientists engaged in all areas of cancer research in the United States and in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. AACR's Annual Meetings attract more than 15,000 participants who share new and significant discoveries in the cancer field. Specialty meetings, held throughout the year, focus on the latest developments in all areas of cancer research.

Source: (this is a press release).

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