Health and Prostate

Overview. The proteasome is a novel target for cancer drugs, and clinical studies in myeloma have generated intense excitement in this field. Because the proteasome interacts with many proteins (as described in the next section), research into the downstream consequences of drugs that inhibit this target is ongoing. Mechanism Of Action. Proteasomes are enzyme complexes involved in the disposal of damaged cellular proteins and the degradation of short-lived proteins that regulate cell proliferation, apoptosis, adhesion, angiogenesis, and signal transduction. Accordingly, inhibition of proteasomes can stimulate apoptosis and suppress tumor growth and spread. Regulatory proteins degraded by proteasomes include p53, p21, p27, NF-kB, I-kB, and bcl-2. Down-regulation of the NF-kB survival pathway, activated by anthracyclines, can reverse drug resistance. In preclinical studies, cancer cells appear more susceptible than normal cells to the effects of proteasome inhibition. Bortezomib. Bortezomib (Millennium's Velcade, formerly PS-341, MLN-341, and LDP-341) is a small-molecule proteasome inhibitor Read more [...]

Onyvax's Onyvax-P is a whole-cell allogeneic vaccine in Phase II development in the United Kingdom for CaP. The vaccine consists of three replication-deficient allogeneic cell lines representing cell types from different stages of the disease—primary tumor, secondary disease, and bone metastases. Onyvax plans to start a Phase III trial in the first half of 2005; manufacture of the vaccine for this trial is under way at Berna Biotech. In an open-label Phase II trial involving 26 men with hormone-refractory CaP that had not metastasized to the bone, 11 patients were vaccinated monthly for one year. The profile of the patient group was favorable: median age was 67, median PSA at presentation was 11.1 ng / mL, and performance status was 0. Each month, patients received a mixture of the three cell lines (8 x 106 of each) supplemented with bacillus Calmette-Guerin (BCG) on weeks 0 and 2, followed by the three lines alone. All 11 patients experienced a prolonged reduction in PSA velocity. Median progression-free survival was 58 weeks. The most frequent side effects were fatigue and local injection-site Read more [...]

Provenge (formerly APC-8015) is a dendritic cell-based vaccine in Phase III development by Dendreon. The company prepares the vaccine by isolating dendritic cells (an important element of the immune system) from a patient's blood and then incubating them with a fusion protein comprising prostatic acid phosphatase (PAP) and a dendritic cell-targeting element, which is structurally similar to GM-CSF. The vaccine is prepared over 48 hours. When readministered to the patient, these cells "teach" the immune system to search out and destroy PAP-producing cells. Investigations have confirmed that the key target for Provenge therapy—PAP—is expressed by 95% of CaP tumors (Small EJ, 2003). On the basis of Phase II trials demonstrating that Provenge is safe and well tolerated and induces antigen immunity, Dendreon initiated three Phase III trials: two trials (DD-901 and DD-902B) involve patients with hormone-refractory metastatic CaP; the third trial (P-l 1) involves patients with rising PSA but without signs of metastases. The ongoing DD-902B trial is designed to confirm DD-901 's findings that Provenge Read more [...]

Overview. The development of vaccines is one of the most active areas of CaP research. Each of the vaccines described in the following paragraphs has demonstrated it can induce the desired immune response. The first two vaccines discussed here—Dendreon's Provenge and Cell Genesys's GVAX—have also shown preliminary evidence of a survival benefit. The third, Onyvax's Onyvax P, has shown a benefit in time to disease progression in early trials. Note that Provenge and GVAX are being tested in combination with docetaxel, the most potent chemotherapeutic agent used to treat CaP. Although vaccines are being tested in late-stage disease, they may ultimately find their place earlier in the course of disease in patients experiencing biochemical relapse (rising PSA), either in combination with hormone therapy or alone, thereby enabling hormone therapy to be kept in reserve. In addition, patients may potentially receive more than one vaccine, either concurrently or consecutively. The following sections discuss only vaccines that have demonstrated benefit in terms of PSA response. Other vaccines in Read more [...]

Atrasentan (Abbott Laboratories' Xinlay, formerly ABT-627) is an oral, small-molecule, selective ET-A-receptor antagonist that appears to slow the progression of CaP. It is in Phase III trials, and Abbott submitted a new drug application (NDA) for the drug with the FDA at the end of 2004. In June 2001, two 1,000-patient international Phase III trials began. Trial M00-211 involved patients with metastatic, hormone-refractory CaP, and trial M00-244 involved patients with nonmetastatic hormone-refractory CaP. In both trials, patients were randomized to receive 10 mg atrasentan or placebo once daily. An Independent Data Monitoring Committee found trial M00-211 failed to meet its primary endpoint of time to disease progression and stopped the trial early despite improvements in several surrogate markers. M00-244 has completed accrual and is ongoing. Meanwhile, a Phase II study (M01-366) is investigating the safety and efficacy of atrasentan among approximately 200 men with hormone-naive CaP and rising PSA (0.4-5.0 ng / mL and a doubling time of less than one year). Abbott has been granted fast-track Read more [...]

Overview. Endothelin-receptor antagonists represent a new generation of oral, targeted, cytostatic agents. They have huge commercial potential if they can successfully negotiate the obstacles to development: demonstration of efficacy in terms of an end point that regulatory agencies deem is sufficiently clinically relevant. Endothelins are part of a family of autocrine / paracrine peptides (ET-1, ET-2, and ET-3) that are potent vasoconstrictors. They are produced from precursor proteins upon cleavage by metalloproteinase endothelin-converting enzymes. An increase in ET-1 protein expression is found in both primary and metastatic CaP tumor sites. Atrasentan (Abbott Laboratories' Xinlay), discussed further on, is the ET-A-receptor antagonist that has progressed furthest in development for CaP. A second ET-A-receptor antagonist in development for CaP is AstraZeneca' s ZD-4054, which is in Phase II trials, but the lack of published clinical data precludes further discussion of this agent. Mechanism Of Action. ET-1 stimulates tumor-cell and osteoblast proliferation, inhibits apoptosis, and stimulates Read more [...]