Rapamycin, an immunosuppressant drug commonly used to prevent rejection in organ transplantation, has shown potential to inhibit tumor growth in many childhood cancers during in vitro and in vivo laboratory studies. However, studies have also suggested that in combination with chemotherapeutic agents commonly used to treat cancer, rapamycin may cause the agents to be ineffective.
Rapamycin has been previously tested in combination with cytotoxic agents. However, none of these studies were performed in vivo nor did they include any agents frequently used in the curative therapy of childhood cancer.
In a study appearing in Molecular Cancer Therapeutics, the Pediatric Preclinical Testing Program (PPTP) used in vitro and in vivo models to evaluate rapamycin combined with agents used frequently in the treatment of childhood cancers. The PPTP is a comprehensive program to systematically evaluate new agents against childhood solid tumor and leukemia models, and is led by Peter Houghton, PhD, director of the Center for Childhood Cancer at The Research Institute at Nationwide Children’s Hospital.
During the study, rapamycin was evaluated in combination with three agents frequently used to treat childhood cancer: cyclophosphamide, cisplatin and vincristine. The combinations were tested in vivo against 12 solid tumor models previously shown to be sensitive to any of the three agents. The combinations were also tested in three models of acute lymphoblastic leukemia.
Findings revealed that during in vivo testing, the addition of rapamycin to cyclophosphamide and to vincristine resulted in therapeutic enhancement in numerous animal models of childhood cancer. The combination of rapamycin with cyclophosphamide appeared most therapeutic. However, therapeutic enhancement was rarely observed when cyclophosphamide was used at levels significantly below its maximum tolerated dose.
“This highlights the importance of using agents at or near their maximum tolerated dose in combination studies,” said Dr. Houghton. “It has been observed clinically that many doses of chemotherapeutic agents must be substantially reduced when being combined with full doses of new agents. The clinical success of a rapamycin, cyclophosphamide combination will depend on whether or not children can tolerate full doses of both drugs."
Unlike cyclophosphamide and vincristine, the combination of rapamycin with cisplatin was associated with markedly increased toxicity. None of the three combinations were shown to enhance therapy in the leukemia models. However, there was strong evidence for slightly improved therapy using a fourth combination involving dexamethasone.
“Some of the models showed consistent evidence of moderately improved therapy, suggesting that there is a subset of tumors for which combinations of cytotoxic agents and rapamycin may be particularly effective,” said Dr. Houghton. “Our goal is to develop a dataset to inform clinical prioritization for a wide range of drug combinations. These results will be useful in planning combination clinical trials.”Houghton PJ, Morton CL, Gorlick R, Lock RB, Carol H, Reynolds CP, Kang MH, Maris JM, Keir ST, Kolb EA, Wu J, Wozniak AW, Billups CA, Rubinstein L, Smith MA. Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Ther. 2010 Jan;9(1):101-12. Epub 2010 Jan 6.