This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SAHA is an inhibitor of histone deacetylase (HDAC) that causes the arrest of cell cycle transition at G1 and G2M phases. SAHA binds to HDAC by inserting a hydroxamic group, most of the aliphatic chain and part of the phenyl amino group in the active site of the enzyme. The insertion of SAHA into the active site prevents the binding of the natural substrate and blocks enzymatic deacetylation. It has been reported to selectively induce expression of p21 waf/CIP1 cyclin dependent kinase inhibitor, to effect cell cycle arrest and to induce p53 independent apoptosis. A possible model for the antitumor action of SAHA is the inhibition of HDAC activity and subsequent accumulation of acetylated histones, and the activation of transcription of genes whose expression causes induction of differentiation or apoptosis and the inhibition of tumor growth. The expression of less than 2% of expressed genes is regulated following exposure to SAHA. The combination of a retinoid acid receptor with a histone deacetylase inhibitor has been shown to have synergistic activity in the treatment of hematological and solid malignancies in both in vitro and in vivo xenograft models. Exposure of HL-60 cells to Trichostatin A (TSA) and 9-cis-RA results in more than additive increase in differentiation. Similarly, the exposure of primary blasts from AML (M2 and M4) patients to TSA restored retinoid-dependent transcriptional activation and led to terminal differentiation. The combination of the HDAC inhibitor, CBHA, with all-trans RA led to synergistic cytotoxicity against neuroblastoma cell lines in vitro and xenograft in vivo models. Preliminary studies of SAHA combined with 13-cis RA have shown synergistic activity in pediatric transformed cell lines such as neuroblastoma, rhabdomyosarcoma and medulloblastoma and primary brain tumor cell lines (personal communication, Olson laboratory.) Retinoid acid receptors recruit co-regulatory complexes with HDAC activity in the absence of a ligand, which results in repression of gene transcription. SAHA: Several phase I/II studies have been conducted in adults. In a phase I trial of SAHA in patients with advanced solid and hematological malignancies, several oral schedules were evaluated including 200-600 mg daily or bid,300- 400 mg bid for 3 days each week. Sixty-two patients were enrolled on this study. The MTD and the recommended phase II dose in adults has been established at 400 mg daily, 200 mg bid or 300 mg bid x 3 days every week. The dose limiting toxicities were non-hematologic (anorexia, dehydration, diarrhea, and fatigue) in both solid tumor and hematological malignancy patients. Non-dose-limiting hematological toxicities included anemia and thrombocytopenia, which were rapidly reversible after drug interruption. A phase I trial in patients with advanced leukemia or myelodysplastic syndrome is ongoing, with dose levels starting at 100 mg-300 mg tid x 14 consecutive days every 21 days. The initial dose was 100 mg tid with dose escalation in increments of 50 mg tid. Fifteen patients have been treated and are evaluable for toxicity. No patient has experienced grade 3 or 4 toxicity or death related to SAHA. Based on these data, several phase II trials in adults are now ongoing at the recommended dose of 400 mg po daily. The adult phase II recommended dose of 400 mg daily has been used as a basis for the starting dose of this protocol. 13-cis Retinoic Acid: Pediatric Studies A Phase I trial of 13-cis RA in pediatric patients established the MTD of 160 mg/m2/day. Dose limiting toxicities of 13- cisRA observed in this pediatric phase I trial included rash and hypercalcemia. A Phase II clinical trial of 13-cis RA at 100 mg/m2/day administered to pediatric patients with recurrent or progressive neuroblastoma revealed minimal anti- tumor activity. However, administration of 13-cisRA at 160 mg/m2/day twice daily for 2 weeks monthly, over a period of six months following consolidation therapy improved event free survival at three years, from 29% in the control cohort to 45% in patients receiving 13-cisRA. The dose and schedule of retinoids proposed in this trial will be identical to that previously used in Phase III pediatric trials. Given the above noted limited side effects observed in children receiving RA, we anticipate that the proposed combination of 13-cis retinoic acid and SAHA will be well tolerated. The primary aims of this study are: 1. To estimate the maximum tolerated dose (MTD) of SAHA administered once daily orally for 28 days to children with refractory or recurrent solid tumors; 2. To estimate the maximum tolerated dose (MTD) of SAHA administered once daily orally for 28 days in combination with 13-cis retinoic acid to children with refractory or recurrent neuroblastoma, medulloblastoma/ CNS neuroectodermal tumor (PNET) or atypical teratoid rhabdoid tumor (ATRT); 3. To assess the tolerability of the solid tumor MTD in patients with recurrent or refractory leukemia; 4. To define and describe the toxicities of SAHA administered on this schedule as a single agent and in combination with 13 cis-retinoic acid; and 5. To characterize the pharmacokinetics of SAHA in children with refractory cancer. Secondary aims are: 1. To preliminarily define the antitumor activity of SAHA as a single agent and in combination with 13-cis retinoic acid within the confines of a Phase 1 study; 2. To assess the biologic activity of SAHA by measuring histone acetylation status in peripheral mononuclear cells (PMNC) and tumor tissue specimens; and 3. To explore the effect of genetic polymorphisms (e.g., UGT1A1) on the pharmacokinetics of
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