Phase II Trial of the CDK4 Inhibitor PD0332991 in Patients With Advanced CDK4-Amplified Well-Differentiated or Dedifferentiated Liposarcoma
Mark A. Dickson,William D. Tap,Mary Louise Keohan,Sandra P. D'Angelo,Mrinal M. Gounder,Cristina R. Antonescu,Jonathan Landa,Li-Xuan Qin,Dustin D. Rathbone,Mercedes M. Condy,Yelena Ustoyev,Aimee M. Crago,Samuel Singer,Gary K. Schwartz +13 more
TLDR
Treatment with theCDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy.Abstract:
Purpose CDK4 is amplified in 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS.read more
Citations
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Cellular senescence: from physiology to pathology.
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The history and future of targeting cyclin-dependent kinases in cancer therapy
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References
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Subtype specific prognostic nomogram for patients with primary liposarcoma of the retroperitoneum, extremity, or trunk.
Kimberly Moore Dalal,Michael W. Kattan,Cristina R. Antonescu,Murray F. Brennan,Samuel Singer +4 more
TL;DR: The LS-specific nomogram based on histologic subtype provides more accurate survival predictions for patients with primary LS than the previously established generic sarcoma nomogram.
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Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR.
Nicolas Sirvent,Jean-Michel Coindre,Georges Maire,Isabelle Hostein,Frédérique Keslair,Louis Guillou,Dominique Ranchère-Vince,Philippe Terrier,Florence Pedeutour +8 more
TL;DR: The results indicate that although helpful, IHC alone is often insufficient to solve diagnostic problems and recommends that the evaluation of MDM2-CDK4 amplification using FISH or Q-PCR be used to supplement IHC analysis when diagnosis of adipose tissue tumors is not possible based on clinical and histologic information alone.
Journal ArticleDOI
Phase I Study of PD 0332991, a Cyclin-Dependent Kinase Inhibitor, Administered in 3-week Cycles (Schedule 2/1)
Gary K. Schwartz,Patricia LoRusso,Mark A. Dickson,Sophia Randolph,M N Shaik,Keith D. Wilner,Rachel Courtney,Peter O'Dwyer +7 more
TL;DR: D dose-limiting toxicities and maximum tolerated dose of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro/vivo, were generally well tolerated.
Journal ArticleDOI
Clinical and Molecular Approaches to Well-differentiated and Dedifferentiated Liposarcoma
Aimee M. Crago,Samuel Singer +1 more
TL;DR: Although complete surgical resection is currently the most effective treatment for WDLS and DDLS, the majority of patients with retroperitoneal liposarcoma will eventually have recurrence and die of disease.
Journal ArticleDOI
Gene expression profiling of liposarcoma identifies distinct biological types/subtypes and potential therapeutic targets in well-differentiated and dedifferentiated liposarcoma.
Samuel Singer,Nicholas D. Socci,Grazia Ambrosini,Elliot B. Sambol,Penelope DeCarolis,Yuhsin Wu,Rachael O'Connor,Robert G. Maki,Agnes Viale,Chris Sander,Gary K. Schwartz,Cristina R. Antonescu +11 more
TL;DR: It is shown that Nutlin-3a, an antagonist of MDM2, preferentially induces apoptosis and growth arrest in dedifferentiated liposarcoma cells compared with normal adipocytes, and the promise of using this expression dataset for new drug discovery in liposARcoma is shown.
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