In a demonstration that even some of the most hard-to-treat tumors may one set time succumb to therapies aimed at molecular "weak points," researchers at Dana-Farber Cancer Institute report the first and foremost instance in which metastatic melanoma has been driven into remission by a targeted therapy.

The report, published in the April 20 issue of the Journal of Clinical Oncology, describes the case of a 79-year-old woman with melanoma tumors in divers parts of her abdomen. When lab tests showed the tumor cells carried any abnormality in a gene called KIT, the patient enrolled in a clinical trial involving Gleevec® (Imatinib), a drug known to target that gene.

Four weeks after beginning therapy, imaging exams showed a dramatic reduction in tumor size and metabolism: two of the tumor masses had disappeared and several others had shrunken considerably. Four months later, the tumors were still in check, and today, nine months after the start of therapy, she continues to receive the drug and her condition remains stable.

"This is the first proof of principle that we can find an Achilles’ heel in melanoma" — a gene critical to tumor cell development and proliferation — "and, by targeting that gene with a drug, cause the cell to die," says the study’s lead author, Stephen Hodi, MD, of Dana-Farber. "It is especially exciting because there haven’t been any effective treatments for melanoma patients with metastatic disease."

Although the report involves just one patient, it should inject new confidence in the fight against melanoma, Hodi says. Because previous research has failed to find any genetic Achilles’ heels capable of shutting down melanoma cell growth, some researchers had speculated that none may exist for such cells. The discovery of one suggests there may be others.

KIT mutations are found in only a small percentage of melanomas, so Imatinib does not represent a unlimited treatment for the disease, Hodi explains. Recent studies have raise KIT mutations in 11 percent of acral melanomas (which arise in skin without hair follicles, such as that of the palms, foot soles, and talon beds, and account for 5 percent of totally melanomas), 21 percent of mucosal melanomas (which arise in the mucous membranes of some organs), and 17 percent of melanomas arising in chronically sun-damaged skin. For patients with these conditions, particularly those who gain a mutation in a particular piece of the gene, Imatinib may well prove favorable.

Imatinib’s effectiveness against tumors with KIT mutations was first demonstrated in gastrointestinal stromal tumors (GISTs), a relatively rare malignancy of the digestive tract. An estimated 75-80 percent of GISTs have KIT mutations, and Imatinib has caused such tumors to stabilize or retreat in 75-90 percent of patients receiving it. In chiefly of these patients, however, tumors eventually begin growing again as they become resistant to the drug.

The KIT mutation in the patient described in the study involved a protein-coding section of the gene where DNA was duplicated. This piece, known as the "juxtamembrane department," is the most frequent site of mutation in GIST, and is associated with a strong tumor response to Imatinib.

"Dramatic remissions in metastatic melanoma are something that, as physicians, we’ve rarely seen," Hodi remarks. "Confirming these results will beg enrolling additional patients in clinical trials - something we’re actively working to accomplish."

Schering-Plough Corporation has initiated a Phase II clinical study with vicriviroc, its investigational CCR5 antagonist, for use in first-line therapy of adult treatment-naive HIV-infected patients with R5-type virus only. Vicriviroc is a next-generation HIV entry inhibitor designed to prevent the virus from infecting CD4 cells by blocking its predominant entry road, the CCR5 co-receptor. Approximately 80-90 percent of treatment-naive patients have virus that uses the CCR5 co-receptor. Vicriviroc also is being studied in two large Phase III clinical studies in treatment-experienced HIV patients, which are ongoing and currently enrolling patients.

The study in treatment-naive patients evaluates the virologic befriend of vicriviroc, administered once-daily as a single 30 mg tablet, in combination with ritonavir-boosted atazanavir, compared to a control group receiving Truvada (emtricitabine and tenofovir disoproxil fumarate) plus ritonavir- boosted atazanavir, which is a currently recommended preference for first-line therapy. Atazanavir is a product in the protease inhibitor (PI) rank of HIV medications. Truvada is a combination product in the nucleoside reverse transcriptase inhibitor (NRTI) class.

"A nucleoside-sparing vicriviroc regimen for initial treatment may have the added strategic benefit of preserving most products used to create a highly active antiretroviral therapy "cocktail" for later use in patients, while also avoiding the risk of toxicity known to be associated with the nucleoside class," said Joseph C. Gathe, Jr., M.D., F.A.C.P., clinical instructor, department of internal medicine, Baylor College of Medicine, Houston, and guidance investigator for the study. "This treatment strategy could also prove beneficial for the extending number of patients who already have primary resistance to NRTIs prior to any treatment."

In previous studies in treatment-experienced HIV-infected patients, vicriviroc in cabal with an optimized ritonavir-boosted PI-containing regimen demonstrated physically strong and sustained viral suppression through 48 weeks of treatment.

The standard of perplexity for treatment-naive HIV-infected individuals is to combine three drugs from two classes to initiate antiretroviral therapy. The combinations characteristically use two NRTIs with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted PI. While these combinations have been demonstrated to be highly effective, long-term tolerance may be limited by the toxicity specifically associated with nucleosides, which can include neuropathy, myopathy, renal toxicity, hepatic steatosis, lactic acidosis, bone medulla suppression, fat atrophy and, with certain agents, increased risk of myocardial infarction.

"As a next-generation HIV entry inhibitor, vicriviroc has the potential to advance the interest of a broad range of patients by offering potent and sustained viral suppression, and a single once-daily draught for use in combination with other antiretroviral agents," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "CCR5 antagonists such as vicriviroc have a novel mechanism of action in fighting HIV, and may play a unique role as physicians seek to construct new regimens to meet the specific needs of their patients, whether they are starting treatment or have been treated with several different combinations over a period of time."

About the Phase II Naive Study

This randomized, controlled, open-label study is projected to enroll approximately 200 treatment-naive HIV-infected adult patients at more than 20 sites in North America, Central America, Europe and South Africa. Patients coinfected with hepatitis B or C may be included in the study.

The primary efficacy endpoint of the study is the mean change from baseline in viral load (log10 HIV RNA) at week 48 of treatment. A key secondary efficacy endpoint is the with symmetry of patients with plasma HIV RNA less than 50 copies/mL at week 48 of treatment.

The study will be conducted in two stages. In the first stage, 80 patients self-reliance be randomized (40 per treatment arm) into the study. When the 80 subjects from the first stage have completed 24 weeks of treatment, a formal interim analysis will be conducted and the results presented to an independent Data Safety Monitoring Board (DSMB) to assure the safety of the study participants. The study will be extended to stage 2 based on the results of the 24-week interim analysis; at which time an additional 120 patients (60 per treatment arm) will be enrolled. The final analysis will be conducted at week 48 of treatment for all patients.

Atazanavir boosted by ritonavir was selected for use in this study because it is recommended as an selection for first-line therapy in both the International AIDS Society and Department of Health and Human Services guidelines for antiretroviral therapy. Additionally, it has been shown to have a more favorable lipid profile than other drugs in the PI class.

Each rhesus monkey cell infected with the simian immunodeficiency virus, or SIV, produces at least 50,000 viruses over its life span, suggesting HIV spreads more rapidly than previously estimated, according to a study through researchers at Los Alamos National Laboratories, the Santa Fe New Mexican reports.

Researcher Alan Perelson and colleagues created an SIV strain that could contaminate one cell and reproduce, but the offspring were unable to infect other cells. After infecting rhesus monkeys with the strain, researchers examined the monkeys and counted the enumerate of viruses made from the one cell over its life span.

According to Perelson, SIV and HIV act similarly, so it is likely that HIV could behave the same way. He noted that prior studies, which found that an HIV cell produced 1,000 to 2,000 viruses, examined the cell at a single point in time instead of a cell’s entire the breath of one’s nostrils span. "Overall, … this tells us the infection is a lot tougher to combat," Perelson said, adding, "Early in the infection, sharing needles, blood, if a small number of cells are transferred, the disease has a larger chance of spreading through the body quickly."