Temsirolimus and valproic acid trial for relapse neuroblastoma opens

New trial for neuroblastoma opens at University of North Carolina – Chapel Hill

Temsirolimus and Valproic Acid in Treating Young Patients With Relapsed Neuroblastoma, Bone Sarcoma, or Soft Tissue Sarcoma

This phase I study will enroll 20 patients age 2 to 18 to determine the maximum tolerated dose of temsirolimus in combination with valproic acid, as well as safety, pharmacokinetics, and progression-free survival. Principal investigator is Dr Julie Blatt.

Valproic acid (VPA) has been used to treat epilepsy for decades. Recent research has show VPA to be a histone deacetylase inhibitor (HDACi), cell cycle modulator, and an antiangiogenetic agent. VPA also induces tumor cell death. Czech researchers published in March 2010 :

Preclinical data suggest that the anticancer effect of chemotherapy is augmented when VPA is used in combination with cytostatics. Besides the effects of pretreatment with HDAC inhibitors, which increases the efficiency of 5-aza-2′-deoxycytidine, VP-16, ellipticine, doxorubicin and cisplatin, pre-exposure to VPA increases the cytotoxicity of topoisomerase II inhibitors. There are two suggested cell death mechanisms caused by potentiation of anticancer drugs by HDAC inhibitors that are neither exclusive nor synergistic. The first involves apoptosis and can be both p53 dependent or independent; the second involves mechanisms other than apoptosis. In resistant chronic myeloid leukemia (CML), VPA restores sensitivity to imatinib. We have demonstrated the synergistic effects of VPA and cisplatin in neuroblastoma cells. VPA can be taken orally, crosses the blood brain barrier and can be used for extended periods.[1]

There are 229 valproic acid clinical trials listed in the NIH database; 68 are recruiting and 26 are for cancer conditions. There are 88 temsirolimus trials currently open to treat cancer.

In 2008 Italian researchers reported on the mechanism of cell death from valproic acid on 2 NB cell lines:

To our knowledge, this is the first demonstration of an HDAC inhibitor-dependent activation of the p53 pathway in neuroblastoma cells known for an abnormal p53 function that is responsible for their resistance to chemotherapy. As a consequence of this ability to restore p53 function, we consider HDAC inhibitors to be a promising class of drugs for the treatment of chemoresistant neuroblastoma tumours.[2]

Temsirolimus is a specific inhibitor of mTOR (mammalian target of rapamycin) and interferes with the synthesis of proteins that regulate proliferation, growth, and survival of tumor cells. FDA approval was granted in 2007 for the treatment of advanced renal cell carcinoma. It was used previously in a frontline NB study at St Jude’s. The NIH clinical trials site currently lists 15 open trials for children with solid tumors using temsirolimus in combination with a wide range of other agents.

There is apparently no published data (or submitted meeting abstracts) in the medical literature for the preclinical work using the combination of temsirolimus and valproic acid on cancer cell lines.

References

1. Curr Drug Targets. 2010 Mar;11(3):361-79. Valproic Acid in the complex therapy of malignant tumors. PMID: 20214599

2. Br J Pharmacol. 2008 Feb;153(4):657-68. Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. PMID: 18059320 [free fulltext]