Reference Detail

Ref Type

Journal Article

PMID

(21173237)

Authors

Smith ME, Cimica V, Chinni S, Jana S, Koba W, Yang Z, Fine E, Zagzag D, Montagna C, Kalpana GV

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	108	1	2011 Jan 4	319-24	Proc Natl Acad Sci U S A

URL

Abstract Text

Rhabdoid tumors (RTs) are rare, highly aggressive pediatric malignancies with poor prognosis and with no standard or effective treatment strategies. RTs are characterized by biallelic inactivation of the INI1 tumor suppressor gene. INI1 directly represses CCND1 and activates cyclin-dependent kinase (cdk) inhibitors p16(Ink4a) and p21(CIP). RTs are exquisitely dependent on cyclin D1 for genesis and survival. To facilitate translation of unique therapeutic strategies, we have used genetically engineered, Ini1(+/-) mice for therapeutic testing. We found that PET can be used to noninvasively and accurately detect primary tumors in Ini1(+/-) mice. In a PET-guided longitudinal study, we 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, and one of the resistant tumors overexpressed cyclin D1, more than flavopiridol-sensitive cells. The concentration of flavopiridol used was not sufficient to down-modulate the high level of cyclin D1 and failed to induce cell death in the resistant cells. Furthermore, FISH and PCR analyses indicated that there is aneuploidy and increased CCND1 copy number in resistant cells. These studies indicate that resistance to flavopiridol may be correlated to elevated cyclin D1 levels. Our studies also indicate that Ini1(+/-) mice are valuable tools for testing unique therapeutic strategies and for understanding mechanisms of drug resistance in tumors that arise owing to loss of Ini1, which is essential for developing effective treatment strategies against these aggressive tumors.

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Molecular Profile	Treatment Approach
SMARCB1 del	MRX34
SMARCB1 T72Qfs*13	CDK Inhibitor (Pan)
SMARCB1 T118Pfs*25	MRX34
SMARCB1 T72Nfs*4	CDK Inhibitor (Pan)
SMARCB1 T72Qfs*13	MRX34
SMARCB1 loss	MRX34
SMARCB1 T118Pfs*25	CDK Inhibitor (Pan)
SMARCB1 E31V	CDK Inhibitor (Pan)
SMARCB1 loss	CDK Inhibitor (Pan)
SMARCB1 T72Nfs*4	MRX34
SMARCB1 Q18*	CDK Inhibitor (Pan)
SMARCB1 L166Pfs*4	CDK Inhibitor (Pan)
SMARCB1 Q18*	MRX34
SMARCB1 R53*	MRX34
SMARCB1 R53*	CDK Inhibitor (Pan)
SMARCB1 del	CDK Inhibitor (Pan)
SMARCB1 E31V	MRX34

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References