Modeling and antitumor studies of a modified L-penetratin peptide targeting E2F in lung cancer and prostate cancer.

E2F1-3a overexpression due to amplification or to mutation or loss of the retinoblastoma gene, induces genes involved in DNA synthesis and leads to abnormal cellular proliferation, tumor growth, and invasion. Therefore, inhibiting the overexpression of one or more of these activating E2Fs is a recognized target in cancer therapeutics. In previous studies we identified by phage display, a novel 7-mer peptide (PEP) that bound tightly to an immobilized consensus E2F1 promoter sequence, and when conjugated to penetratin to increase its uptake into cells, was cytotoxic to several malignant cell lines and human prostate and small cell lung cancer xenografts.

Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity.

TAM receptors (Tyro-3, Axl, and Mertk) are a family of three homologous type I receptor tyrosine kinases that are implicated in several human malignancies. Overexpression of TAMs and their major ligand Growth arrest-specific factor 6 (Gas6) is associated with more aggressive staging of cancers, poorer predicted patient survival, acquired drug resistance and metastasis. Here we describe small molecule inhibitors (RU-301 and RU-302) that target the extracellular domain of Axl at the interface of the Ig-1 ectodomain of Axl and the Lg-1 of Gas6.

NAD+ Kinase as a Therapeutic Target in Cancer.

NAD kinase (NADK) catalyzes the phosphorylation of nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide phosphate (NADP) using ATP as the phosphate donor. NADP is then reduced to NADPH by dehydrogenases, in particular glucose-6-phosphate dehydrogenase and the malic enzymes. NADPH functions as an important cofactor in a variety of metabolic and biosynthetic pathways.

BMI-1 Targeting Interferes with Patient-Derived Tumor-Initiating Cell Survival and Tumor Growth in Prostate Cancer.

Purpose: Current prostate cancer management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TIC-tailored therapies appears to be a promising approach.

Axl receptor tyrosine kinase is up-regulated in metformin resistant prostate cancer cells.

Recent epidemiological studies showed that metformin, a widely used anti-diabetic drug might prevent certain cancers. Metformin also has an anti-proliferative effect in preclinical studies of both hematologic malignancies as well as solid cancers and clinical studies testing metformin as an anti-cancer drug are in progress. However, all cancer types do not respond to metformin with the same effectiveness or acquire resistance.

Darinaparsin inhibits prostate tumor-initiating cells and Du145 xenografts and is an inhibitor of hedgehog signaling.

Prostate cancer is the leading cause of cancer-related death in men in the United States. A major cause of drug resistance in prostate and other epithelial tumors may be due to the presence of a fraction of tumor cells that retain the ability to initiate tumors and hence are termed tumor-initiating cells (TIC) or cancer stem cells. Here, we report that darinaparsin, an organic derivative of arsenic trioxide, is cytotoxic to prostate cancer cell lines as well as fresh prostate cancer cells from patients at low micromolar concentrations, and importantly inhibits the TIC subpopulations.

A novel peptide that inhibits E2F transcription and regresses prostate tumor xenografts.

E2F-1, a key transcription factor necessary for cell growth, DNA repair and differentiation, is an attractive target for development of useful anticancer drugs in tumors that are E2F "oncogene addicted". A peptide, isolated from phage clones, based on its binding to an E2F-1 consensus sequence, was cytotoxic against a wide range of cancer cell lines. The peptide was coupled to penetratin (PEP) and tested against prostate cancer cell lines, and a fresh sample from a patient with metastatic cancer.

Enrichment of human prostate cancer cells with tumor initiating properties in mouse and zebrafish xenografts by differential adhesion.

Background: Prostate tumor-initiating cells (TICs) have intrinsic resistance to current therapies. TICs are commonly isolated by cell sorting or dye exclusion, however, isolating TICs from limited primary prostate cancer (PCa) tissues is inherently inefficient. We adapted the collagen adherence feature to develop a combined immunophenotypic and time-of-adherence assay to identify human prostate TICs.

Species-specific differences in translational regulation of dihydrofolate reductase.

We have observed that rodent cell lines (mouse, hamster) contain approximately 10 times the levels of dihydrofolate reductase as human cell lines, yet the sensitivity to methotrexate (ED(50)), the folate antagonist that targets this enzyme, is similar. Our previous studies showed that dihydrofolate reductase protein levels increased after methotrexate exposure, and we proposed that this increase was due to the relief of feedback inhibition of translation as a consequence of methotrexate binding to dihydrofolate reductase. In the current report, we show that unlike what was observed in human cells, dihydrofolate reductase (DHFR) levels do not increase in hamster cells after methotrexate exposure.

Tumor initiating cells.

Cancer Stem cells (CSC) are defined as a population of cells found within a tumor that have characteristics similar to normal stem cells. Like normal stem cells they have the potential to self renew and differentiate. The cellular origin of these cancer stem cells--whether they originate from stem cells that have lost the ability to regulate proliferation, or they arise from more differentiated population of progenitor cells that have acquired abilities to self-renew is still unclear.