Identification of compounds that inhibit growth of 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine-resistant cancer cells.

The dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) is a heterocyclic amine and is a common byproduct of cooked meat and fish. Although most cells undergo apoptosis when exposed to this mutagen, subsets develop resistance. Rather than die, these resistant cells persist and accumulate mutations, thereby driving tumorigenesis of exposed organs within the gastrointestinal tract. By applying a high-throughput cell-based screen of 32,000 small molecules, we have identified a family of compounds that specifically inhibit the growth of PhIP-resistant cancer cells. These compounds may prove useful for the treatment or prevention of gastrointestinal tumors arising after exposure to PhIP and related carcinogens.

PRL-3 expression in metastatic cancers.

PURPOSE: Expression of the PRL-3 tyrosine phosphatase is elevated in liver metastases derived from colorectal cancer (CRC). We sought to determine the cellular basis of this elevation and assess the expression of PRL-3 in metastatic lesions derived from cancers of the colon and other tissues. EXPERIMENTAL DESIGN: We developed modifications of in situ hybridization methods that facilitated the study of paraffin-embedded sections. We also evaluated PRL-3 gene copy numbers using fluorescence in situ hybridization and developed antibodies to assess PRL-3 subcellular localization. RESULTS: PRL-3 mRNA expression was elevated in nearly all metastatic lesions derived from CRCs, regardless of the site of metastasis (liver, lung, brain, or ovary). Expression was found in neoplastic cells, although tumor endothelium also expressed the gene. In contrast, little or no PRL-3 expression was observed in normal colon, nonmetastatic primary cancers, or metastatic lesions derived from cancers other than those of the colon (pancreas, stomach, or esophagus). Interphase fluorescence in situ hybridization confirmed that gene amplification was not the major cause of PRL-3 overexpression. Immunohistochemical analysis with anti-PRL-3 antibodies showed a cell membrane localization, consistent with the predicted isoprenylation of the protein. CONCLUSIONS: These studies establish an unexpected and unprecedented specificity in metastatic gene expression profiles: PRL-3 is apparently expressed in CRC metastases to any organ but is not expressed in metastases of other cancers to the same organs or in nonmetastatic CRCs. PRL-3 is also expressed in tumor vasculature, regardless of the tumor source. These data raise intriguing questions about the role of protein phosphorylation in angiogenesis and cell-type-specific metastatic processes.

New paradigms for cancer drug discovery.

This article was previously published in Cancer Biol Ther 2(4):452-455. Discovering drugs has never been an easy task. Traditionally, this task has exclusively been undertaken by large pharmaceutical companies that recovered their high RD costs by selling expensive medications. Despite the huge amount of time and effort devoted towards drug discovery over the last decade, the successful therapy of cancer has been limited. There are signs that the approach of how to discover drugs might change, especially in the field of cancer. Recently, several academic institutions have started to develop their own drug discovery programs. By pointing out the critical elements of the cancer drug discovery process, we examine why it would not be a surprise if some future cancer drugs will come out of academic research institutions and complement the ones developed by big pharma.

New paradigms for cancer drug discovery.

Discovering drugs has never been an easy task. Traditionally, this task has exclusively been undertaken by large pharmaceutical companies that recovered their high research and development costs by selling expensive medications. Despite the huge amount of time and effort devoted towards drug discovery over the last decade, the successful therapy of cancer has been limited. There are signs that the approach of how to discover drugs might change, especially in the field of cancer. Recently, several academic institutions have started to develop their own drug discovery programs. By pointing out the critical elements of the cancer drug discovery process, we examine why it would not be a surprise if some future cancer drugs will come out of academic research institutions and complement the ones developed by big pharma.

PRL-3: a phosphatase for metastasis?

The PRL-3 phosphatase has joined the cancer arena very recently but is rapidly gaining interest both as a putative prognostic factor and as a therapeutic target for metastatic tumors. In this issue Guo and colleagues provide another key piece of information by showing that the catalytic activity of PRL-3 is required for experimental metastasis formation in mouse models. Here we summarize the current knowledge and discuss what remains to be done before PRL-3 could be considered as a target for diagnostics or therapeutics in the clinical setting of human cancer.

A phase I safety and pharmacokinetic study of the death receptor 5 agonistic antibody PRO95780 in patients with advanced malignancies.

PURPOSE: PRO95780 is a fully human IgG1 monoclonal antibody that triggers the extrinsic apoptosis pathway through death receptor 5. This first-in-human study assessed the safety, tolerability, pharmacokinetics, and any early evidence of efficacy of PRO95780 in patients with advanced malignancies. EXPERIMENTAL DESIGN: Target concentrations were predicted to occur at 10 mg/kg. Patients received up to eight cycles of PRO95780 i.v. using a 3+3 dose escalation design at 1 to 20 mg/kg every 14 days (every 28 days in cycle 1; stage 1), with cohort expansion at either the maximum tolerated dose or 10 mg/kg, whichever was lower (stage 2). Patients were evaluated for response every other cycle. RESULTS: The maximum tolerated dose was not reached within this study. Four (8%) of 50 patients reported adverse events of greater than grade 2 at least possibly related to PRO95780, including 2 patients with reversible grade 3 transaminase elevation. The mean terminal half-life was 8.8 to 19.3 days, with dose-dependent increases in exposure (peak plasma concentration and area under the concentration) across 1 to 15 mg/kg. Most patients treated with 10 mg/kg or above achieved trough concentration above the target efficacious concentration at day 15 with moderate accumulation after multiple doses. No objective responses occurred, although three minor responses were observed in patients with colorectal and granulosa cell ovarian cancers (each treated with 4 mg/kg) and chondrosarcoma (10 mg/kg). CONCLUSIONS: PRO95780 is safe and well tolerated at doses up to 20 mg/kg. Evidence of activity was noted in several different tumor types at 4 and 10 mg/kg. Pharmacokinetic analysis supports a dosing regimen of 10 to 15 mg/kg every 2 to 3 weeks.

Will targeted therapy hold its promise? An evidence-based review.

(1) Many of the significant advances in cancer management in recent years have centered on the development and introduction of molecularly targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors.(2) Despite targeted therapy that has clearly benefited and even cured certain patients (eg, imatinib, trastuzumab), the ultimate goal of curing cancer, and the more immediate goal of replacing non-targeted chemotherapies with less toxic, targeted agents has yet to be achieved for most cancer patients.(3) Based on a systematic review of randomized controlled trials, examples of significant benefits in selected cancers are provided:(a) Non-Hodgkin's lymphoma (NHL) - A large meta-analysis and several individual randomised, controlled trials (RCTs) report that rituximab plus chemotherapy has a major survival advantage over chemotherapy alone in patients with NHL; an overview of six clinical trials supports the survival benefit of rituximab plus chemotherapy.(b) Renal cell carcinoma (RCC) - Temsirolimus or sunitinib has a significant survival benefit relative to interferon-alpha, and sorafenib carries such a benefit in patients resistant to standard therapy.(c) Colorectal cancer (CRC) - An overview of three RCTs in metastatic CRC revealed that bevacizumab plus 5-fluorouracil/leucovorin possesses a significant survival advantage over 5-fluorouracil/leucovorin and irinotecan/5-fluorouracil/leucovorin.(d) Non-small-cell lung cancer (NSCLC) - In refractory NSCLC, erlotinib significantly prolongs survival, particularly in nonsmokers, and gefitinib may have some utility in patients of Asian ethnicity.(e) Head and neck squamous-cell carcinoma (HNSCC) - Cetuximab plus radiotherapy (versus radiotherapy alone) significantly improves locoregional control and survival (hazard ratio [HR] 0.68; p = 0.005) without worsening radiotherapy-related toxicity.

Discodermolide analogues as the chemical component of combination bacteriolytic therapy.

The marine natural product (+)-discodermolide (1) and several simplified analogues of this microtubule-stabilizing agent have proven to be potent in vitro cell growth inhibitory agents in several human cancer cell lines. Here, we demonstrate the in vivo efficacy of discodermolide and several simplified congeners, both as stand-alone anti-tumor agents and, in the case of (+)-2,3-anhydrodiscodermolide (3), as a chemical component of the combination bacteriolytic therapy. A single intravenous injection of (+)-3 plus genetically modified Clostridium novyi-NT spores caused rapid and complete regressions of tumors in mice bearing HCT116 colorectal cancer xenografts.

Mutational analysis of the tyrosine phosphatome in colorectal cancers.

Tyrosine phosphorylation, regulated by protein tyrosine phosphatases (PTPs) and kinases (PTKs), is important in signaling pathways underlying tumorigenesis. A mutational analysis of the tyrosine phosphatase gene superfamily in human cancers identified 83 somatic mutations in six PTPs (PTPRF, PTPRG, PTPRT, PTPN3, PTPN13, PTPN14), affecting 26% of colorectal cancers and a smaller fraction of lung, breast, and gastric cancers. Fifteen mutations were nonsense, frameshift, or splice-site alterations predicted to result in truncated proteins lacking phosphatase activity. Five missense mutations in the most commonly altered PTP (PTPRT) were biochemically examined and found to reduce phosphatase activity. Expression of wild-type but not a mutant PTPRT in human cancer cells inhibited cell growth. These observations suggest that the mutated tyrosine phosphatases are tumor suppressor genes, regulating cellular pathways that may be amenable to therapeutic intervention.