Phase I Clinical Trial of 5-Fluoro-Pyrimidinone (5FP), an Oral Prodrug of 5-Fluorouracil (5FU)

Purpose: 5-Fluoro-Pyrimidinone (5FP)is an oral pro-drug of 5-Fluorouracil(5FU), and is converted to 5FU by hepaticaldehyde oxidase. Preclinically, 5FPdemonstrated anti-tumor activity againstcolon 38 and P 388 leukemia models in mice. Using an accelerated titration trial designwith one patient cohorts and initial 100%escalations, a Phase I trial was conductedto determine the maximum tolerated dose(MTD) of 5FP and describe its toxicity andpharmacokinetic profile.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45222/1/10637_2004_Article_390715.pd

Loss of Ubiquitin-Specific Peptidase 18 Destabilizes 14-3-3ζ Protein and Represses Lung Cancer Metastasis

Cancer metastasis is a major cause of cancer-related mortality. Strategies to reduce metastases are needed especially in lung cancer, the most common cause of cancer mortality. We previously reported increased ubiquitin-specific peptidase 18 (USP18) expression in lung and other cancers. Engineered reduction of USP18 expression repressed lung cancer growth and promoted apoptosis. This deubiquitinase (DUB) stabilized targeted proteins by removing the complex interferon-stimulated gene 15 (ISG15). This study explores if the loss of USP18 reduced lung cancer metastasis. USP18 knock-down in lung cancer cells was independently achieved using small hairpin RNAs (shRNAs) and small interfering RNAs (siRNAs). USP18 knock-down reduced lung cancer growth, wound-healing, migration, and invasion versus controls (P \u3c .001) and markedly decreased murine lung cancer metastases (P \u3c .001). Reverse Phase Protein Arrays (RPPAs) in shRNA knock-down lung cancer cells showed that 14-3-3ζ protein was regulated by loss of USP18. ISG15 complexed with 14-3-3ζ protein reducing its stability. Survival in lung adenocarcinomas (P \u3c .0015) and other cancers was linked to elevated 14-3-3ζ expression as assessed by The Cancer Genome Atlas (TCGA). The findings were confirmed and extended using 14-3-3ζ immunohistochemical assays of human lung cancer arrays and syngeneic murine lung cancer metastasis models. A direct 14-3-3ζ role in controlling lung cancer metastasis came from engineered 14-3-3ζ knock-down in lung cancer cell lines and 14-3-3ζ rescue experiments that reversed migration and invasion inhibition. Findings presented here revealed that USP18 controlled metastasis by regulating 14-3-3ζ expression. These data provide a strong rationale for developing a USP18 inhibitor to combat metastases

Advances in using PARP inhibitors to treat cancer

The poly (ADP-ribose) polymerase (PARP) family of enzymes plays a critical role in the maintenance of DNA integrity as part of the base excision pathway of DNA repair. PARP1 is overexpressed in a variety of cancers, and its expression has been associated with overall prognosis in cancer, especially breast cancer. A series of new therapeutic agents that are potent inhibitors of the PARP1 and PARP2 isoforms have demonstrated important clinical activity in patients with breast or ovarian cancers that are caused by mutations in either the BRCA1 or 2 genes. Results from such studies may define a new therapeutic paradigm, wherein simultaneous loss of the capacity to repair DNA damage may have antitumor activity in itself, as well as enhance the antineoplastic potential of cytotoxic chemotherapeutic agents

Phase II trial of fenretinide in advanced renal carcinoma

Purpose : Fenretinide, a synthetic form of retinoid, induced apoptosis even in chemotherapy resistant cell lines. A phase II study was hence conducted to evaluate toxicity and efficacy of fenretinide in metastatic renal cancer. Methods : Eligibility included unresectable or metastatic renal cell carcinoma (RCC), adequate organ function and Zubrod performance status ≦2. Prior immunotherapy and a maximum of one prior chemotherapy regimen were allowed. Fenretinide was administered at a dose of 900 mg/m 2 twice daily orally for 7 days in a 21-day cycle. Toxicity was assessed at the start of each cycle, and response every 2 cycles. Results : Nineteen eligible patients enrolled of which fifteen had visceral/bone metastases. Seventeen patients had prior nephrectomy and 11 had prior immunotherapy. 76 cycles of therapy were delivered. Therapy was very well tolerated with few severe toxicities consisting of thrombosis in 1 individual and grade 3 fatigue, nausea and diarrhea in 1 patient. 5 patients had grade 2 nyctalopia and 3 patients had transient grade 2 visual toxicity. No objective responses were noted. Stable disease was seen in seven of nineteen cases (37%, 90% C.I. 0.21–0.59). Median time to progression was 1.5 months and median duration of stable disease was 5.8 months (90% C.I. 3.0–8.4). Median survival was 10 months. Tumor fenretinide levels were obtained in three patients and were in the lower end of the therapeutic range. Conclusion : Fenretinide was well tolerated but demonstrated minimal activity that was consistent with results of intratumoral drug measurements. Strategies are needed that will increase systemic and tumor levels of fenretinide.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45264/1/10637_2005_Article_5864.pd

Association of changes in expression of HDAC and SIRT genes after drug treatment with cancer cell line sensitivity to kinase inhibitors

ABSTRACTHistone deacetylases (HDACs) and sirtuins (SIRTs) are important epigenetic regulators of cancer pathways. There is a limited understanding of how transcriptional regulation of their genes is affected by chemotherapeutic agents, and how such transcriptional changes affect tumour sensitivity to drug treatment. We investigated the concerted transcriptional response of HDAC and SIRT genes to 15 approved antitumor agents in the NCI-60 cancer cell line panel. Antitumor agents with diverse mechanisms of action induced upregulation or downregulation of multiple HDAC and SIRT genes. HDAC5 was upregulated by dasatinib and erlotinib in the majority of the cell lines. Tumour cell line sensitivity to kinase inhibitors was associated with upregulation of HDAC5, HDAC1, and several SIRT genes. We confirmed changes in HDAC and SIRT expression in independent datasets. We also experimentally validated the upregulation of HDAC5 mRNA and protein expression by dasatinib in the highly sensitive IGROV1 cell line. HDAC5 was not upregulated in the UACC-257 cell line resistant to dasatinib. The effects of cancer drug treatment on expression of HDAC and SIRT genes may influence chemosensitivity and may need to be considered during chemotherapy