Albert Einstein Cancer Center

Therapeutically targeting cyclin D1 in primary tumors arising from loss of Ini1

Rhabdoid tumors (RTs) are rare, highly aggressive pediatric malignancies with poor prognosis and with no standard or effective treatment strategies. These tumors are characterized by biallelic inactivation of the INI1 tumor suppressor gene which directly represses CCND1 and activates cyclin-dependent kinase (cdk) inhibitors p16(Ink4a) and p21(CIP). Rhabdoid tumors are exquisitely dependent on cyclin D1 for genesis and survival. To facilitate translation of unique therapeutic strategies, genetically engineered, Ini1(+/-) mice were employed for evaluating therapeutic strategies using PET longitudinally to noninvasively and accurately detect tumor presence and progression. AECC members Kalpana, Montagna and Fine found that treating Ini1(+/-) mice bearing primary tumors with the pan-cdk inhibitor flavopiridol resulted in complete and stable regression of some tumors. Other tumors showed resistance to flavopiridol, one of which overexpressed cyclin D1. The concentration of flavopiridol used was not sufficient to suppress the high level of cyclin D1 and failed to induce cell death in the resistant cells. FISH and PCR analyses indicated that there was aneuploidy and increased CCND1 copy number in resistant cells. These studies indicated that resistance to flavopiridol may be correlated to elevated cyclin D1 levels and that Ini1(+/-) mice can be  a valuable tool for testing unique therapeutic strategies and for understanding mechanisms of drug resistance in tumors that arise owing to loss of Ini1. 

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