sirolimus and ixabepilone

Since the middle of 1990s, the development of combinatorial chemistry along with the high throughput screening have led to some lack of interest for natural products from the pharmaceutical industry. Moreover, purification and optimization of natural compounds are very often difficult and animal experimentations need enough supply of natural sources or alternatively need sophisticated total synthesis. In oncology, this increased disinterest was also closely connected with the rapid expansion of monoclonal antibodies and synthetic protein kinase inhibitors. However since 2005, with the approval of five new drugs by the FDA (trabectedin, ixabepilone, temsirolimus, everolimus and Vinflunine), it appears that natural products are still present as direct or indirect sources of drugs. On the other hand, a third generation of natural product has arisen, which relies upon bioengineering using genetically altered producer organisms. This is particularly true of the polyketides where bioengineering harnesses their natural flexibility to expand their structural diversity. Several programs are going on to produce antibiotics, anticancer drugs or immunosuppressant. This combinatorial approach makes drug discovery by bioengineering complementary with conventional medicinal chemistry. With the approval of Mylotarg by the FDA, increased interest has also been devoted to immunoconjugates, which represent a way by which highly cytotoxic natural products such as dolastatin, calicheamycin, duocarmycin and maytansin may be targeted to cancer cells while limiting their side-effects.

Topics: Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bioengineering; Biological Products; Clinical Trials as Topic; Combinatorial Chemistry Techniques; Dioxoles; Drug Approval; Drug Discovery; Drug Screening Assays, Antitumor; Drugs, Investigational; Epothilones; Everolimus; Gemtuzumab; Humans; Immunoconjugates; Maytansine; Sirolimus; Tetrahydroisoquinolines; Trabectedin; United States; United States Food and Drug Administration; Vinblastine

Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy.. In this randomized phase II trial, patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) endometrial cancer were randomly assigned to treatment with PC plus bevacizumab (Arm 1), PC plus temsirolimus (Arm 2) or ixabepilone and carboplatin (IC) plus bevacizumab (Arm 3). The primary endpoint was progression-free survival (PFS). Comparable patients on the PC Arm of trial GOG209 were used as historical controls. Secondary endpoints were response rate, overall survival (OS), and safety.. Overall, 349 patients were randomized. PFS duration was not significantly increased in any experimental arm compared with historical controls (p > 0.039). Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63-1.02), 1.22 (0.96-1.55) and 0.87 (0.68-1.11), respectively. Response rates were similar across arms (60%, 55% and 53%, respectively). Relative to controls, OS duration (with censoring at 36 months), was significantly increased in Arm 1 (p < 0.039) but not in Arms 2 and 3; the HRs (92% CIs) were 0.71 (0.55-0.91), 0.99 (0.78-1.26), and 0.97 (0.77-1.23), respectively. No new safety signals were identified. Common mutations and rates of mismatch repair protein loss are described by histotype. Potential predictive biomarkers for temsirolimus and bevacizumab were identified.. PFS was not significantly increased in any experimental arm compared to historical controls. NRG Oncology/Gynecologic Oncology Group Study GOG-86P.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Endometrial Neoplasms; Epothilones; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Sirolimus

Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P.. TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P.. Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53.. This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Clinical Trials, Phase II as Topic; Endometrial Neoplasms; Epothilones; Female; Genes, p53; Humans; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Paclitaxel; Progression-Free Survival; Randomized Controlled Trials as Topic; Sirolimus; Survival Rate; Treatment Outcome; Tumor Suppressor Protein p53

Molecularly targeted therapies have emerged as the leading theme in cancer therapeutics. Multi-cytotoxic drug regimens have been highly successful, yet many studies in targeted therapeutics have centered on a single agent. We investigated whether the Src/Abl kinase inhibitor dasatinib displays synergy with other agents in molecularly heterogeneous breast cancer cell lines. MCF-7, SKBR-3, and MDA-MB-231 display different signaling and gene signatures profiles due to expression of the estrogen receptor, ErbB2, or neither. Cell proliferation was measured following treatment with dasatinib±cytotoxic (paclitaxel, ixabepilone) or molecularly targeted agents (tamoxifen, rapamycin, sorafenib, pan PI3K inhibitor LY294002, and MEK/ERK inhibitor U0126). Dose-responses for single or combination drugs were calculated and analyzed by the Chou-Talalay method. The drugs with the greatest level of synergy with dasatinib were rapamycin, ixabepilone, and sorafenib, for the MDA-MB-231, MCF-7, and SK-BR-3 cell lines respectively. However, dasatinib synergized with both cytotoxic and molecularly targeted agents in all three molecularly heterogeneous breast cancer cell lines. These results suggest that effectiveness of rationally designed therapies may not entirely rest on precise identification of gene signatures or molecular profiling. Since a systems analysis that reveals emergent properties cannot be easily performed for each cancer case, multi-drug regimens in the near future will still involve empirical design.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Breast Neoplasms; Butadienes; Cell Line, Tumor; Chromones; Dasatinib; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Epothilones; Female; Humans; Morpholines; Niacinamide; Nitriles; Paclitaxel; Phenylurea Compounds; Pyridines; Pyrimidines; Signal Transduction; Sirolimus; Sorafenib; Tamoxifen; Thiazoles

Since the late 1990s and the rapid expansion of monoclonal antibodies and synthetic protein kinase inhibitors in oncology, anticancer natural products fell out of fashion with the pharmaceutical industry. But in 2007 with the approval of three new drugs derived from natural products, the emergence of promising antitumor compounds from microorganisms (e.g. alvespimycin, salinosporamide) and the growing importance of new formulations of known natural product-derived drugs (nanoparticle formulations, oral forms), we are witnessing a new wave for natural products in oncology. The recent approval of the microtubule-targeted epothilone derivative ixabepilone (Ixempra), the DNA-alkylating marine alkaloid trabectedin (Yondelis) and the inhibitor of mTOR protein kinase temsirolimus (Torisel) is emblematic of the evolution of the field which combines the long established finding of conventional cytotoxic agents and the emergence of molecularly targeted therapeutics. These three examples also illustrate the increasing importance of microbial sources for the discovery of medically useful natural products. The contribution of innovative biological targets is also highlighted here, with references to proteasome inhibitors and novel approaches such as manipulation of mRNA splicing. Altogether, these observations plead for the return of natural products in oncology.

Topics: Antineoplastic Agents; Biological Products; Dioxoles; Epothilones; Humans; Neoplasms; Sirolimus; Tetrahydroisoquinolines; Trabectedin

In this article, you'll learn about eight new drugs, including: doripenem, an antibiotic for complicated intra-abdominal and urinary tract infections. Maraviroc, a new antiretroviral agent to treat HIV infection. Ixabepilone, a new drug for refractory metastatic breast cancer. Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult the package insert for information about each drug's safety during pregnancy and breast-feeding. Also consult a pharmacist, the package insert, or a comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions for all these drugs.

Topics: Acromegaly; Adult; Anti-Bacterial Agents; Anti-HIV Agents; Antineoplastic Agents; Biopterins; Carbapenems; Child; Child, Preschool; Cyclohexanes; Doripenem; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Epothilones; Humans; Infant; Maraviroc; Peptides, Cyclic; Pharmaceutical Preparations; Phenylketonurias; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Sirolimus; Somatostatin; Triazoles

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Docetaxel; Epothilones; Everolimus; Female; Fluorouracil; Humans; Letrozole; Nitriles; Sirolimus; Tamoxifen; Taxoids; Trastuzumab; Triazoles