The aim of the Molecular Therapeutics Unit (MTU) is the identification of novel biochemical pathways altered in HNSCC leading to the discovery of small molecules, that may modulate molecular events important for oral carcinogenesis, and thus may represent novel chemotherapeutic agents. Furthermore, the unit focuses in the preclinical assessment of biochemical and molecular parameters modulated by these small molecules, which may help to monitor the effects on tumor samples in patients with head and neck cancer receiving these novel treatment modalities. Finally, selected signaling agents developed in the unit are tested in early clinical trials in patients with advanced HNSCC and other malignancies for ?proof of principle testing?, in order to assess whether the preclinical effects observed occur also in humans; novel effects observed in human trials are then, investigated in our unit, ?reverse translation. Molecular and biochemical effects of small molecules cell cycle modulators in patients with advanced neoplasms Searching for available tissues (accessible by non-invasive means), we hypothesized that oral keratinocytes obtained by oral cytobrush may be a good source (surrogate tissue) to study drug effects (surrogate markers). After significant efforts in our lab we are now able to assess the effects of drugs in oral keratinocytes, as measured by western blot, IHC and quantitative PCR methods. We have ?road tested? this methodology in our Phase I trial of perifosine (see below). In order to fully validate the use of oral keratinocytes obtained by cytobrush, we have opened in October 2002 a protocol in our institute ?Molecular, Genetic, and Biochemical Effects Of Novel Therapies In Buccal Mucosal Cells? (03-D-0115) This protocol will test the pharmacodynamic effects of novel agents in oral buccal mucosal cells in patients already enrolled in Phase I and II clinical trials for neoplastic diseases at the Clinical Center. In this study we conduct, in parallel, cytobrushes and punch biopsies from buccal mucosa, at similar time points (before and after therapy) to compare the gene and protein expression profile of those tissues. Some of the subjects will also undergo tumor biopsy, if accessible or available. Genomic and proteomic profiles and post-translational protein modifications will be determined as well. DNA will be extracted from these tissues and will be screened for genetic polymorphisms in several candidate alleles that can affect drug action. Clinical effects (i.e. response, toxicity) will be correlated with biochemical/molecular profiles obtained from keratinocytes (brushes and punch biopsies), PBMCs, and tumors samples, if available. If successful, we will be in a position to export this technology to the extramural world to test and dose novel agents in a more rational way, hopefully, increasing their therapeutic indices. We are currently analyzing samples obtained in collaboration with William Dahut, MD (MOCRU, NCI) from a Phase 2 clinical trial of perifosine in androgen-independent prostate carcinoma. We are currently testing whether PBMCs and/or OK may predict response/toxicities of this agent. In collaboration with Theresa Thalhammer (Univ of Vienna, Austria), we continued our interest in the clinical pharmacology of flavopiridol and UCN-01. Moreover, in collaboration with William Figg, we determined the clinical pharmacology of flavopiridol in patients treated as a 72-hour continuous infusion. Based on our previous preclinical and clinical studies with flavopiridol, in collaboration with NCI/NIDCD, we have completed the accrual of patients to our protocol entitled ?Phase II trial of daily bolus flavopiridol for five consecutive days in patients with recurrent/metastatic squamous cell carcinoma of the Head and Neck (SCCHN). Although we have not reached the first phase of the study (treatment of 9 eligible patients), we decided that, based on the low accrual and antitumor activity of the agent, further patients will not yield positive information. In collaboration with Alter Blanche (NCI), we are participating in collaborative effort to study prospectively a large cohort of patients afflicted with Fanconi Anemia. Patients with Fanconi anemia who survive the hematological complications succumb, in the majority of cases, due to HNSCC. We are evaluating these patients to prospectively determine the molecular and biochemical factors responsible for the malignant transformation in the oropharyngeal tissues.
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