Nieuw medicijn - PD-0332991 - stopt groei hersentumoren Glioblastoom in dierproeven. Zodra gestopt werd met dit medicijn gingen de tumoren weer groeien. Fase I studie bij 33 patienten met nierkanker en lymfklierkanker bevestigt veiligheid van dit middel en geeft bemoedigende resultaten. Artikel update 19 juli 2011
19 juli 2011: vorig jaar kwam het nieuws naar buiten dat een bepaald middel de groei van hersentumoren zou stoppen. Inmiddels is in New York een fase I studie gedaan met dit middel bij patienten met nierkanker en lymfklierkanker. In het academisch ziekenhuis Groningen zijn inmiddels laboratoriumproeven met dit middel gedaan. Hier het abstract van de studie met patienten uit New York:
Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1).
Source
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Abstract
Background:This phase I, open-label, first-in-human study determined dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro/vivo.
Methods:A total of 33 patients with retinoblastoma protein-positive advanced solid tumours or non-Hodgkin's lymphoma refractory to standard therapy or for which no therapy was available received PD 0332991 once daily (QD) for 14 days followed by 7 days off treatment (21-day cycles; Schedule 2/1).
Results:Six patients had DLTs (18%; four receiving 200 mg QD; two receiving 225 mg QD); the MTD was 200 mg QD. Treatment-related, non-haematological adverse events occurred in 29 patients (88%) during cycle 1 and 27 patients (82%) thereafter. Adverse events were generally mild-moderate. Of 31 evaluable patients, one with testicular cancer achieved a partial response; nine had stable disease (10 cycles in three cases). PD 0332991 was slowly absorbed (mean T(max) 4.2 h) and eliminated (mean half-life 26.7 h). Volume of distribution was large (mean 3241 l) with dose-proportional exposure. Using a maximum effective concentration model, neutropenia was proportional to exposure.
Conclusion:PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study.
- PMID:
- 21610706
- [PubMed - in process]
18 april 2010: Bron: Cancer Res. 2010 Apr 15;70(8):3228-38. Epub 2010 Mar 30.
Wetenschappers aan de universiteit van San Fransisco melden dat zij in preklinische studies in het laboratorium alswel bij dieren een medicijn PD-0332991 hebben getest dat de groei van tumoren in de hersenen (glioblastomen) zou stoppen. Uit verschillende studies bleek dat muizen zo lang zij dit medicijn innamen doorleefden met een hersentumor en de tumor zelf niet groeide. Zodra de wetenschappers stopten met dit medicijn gingen de tumoren weer groeien en stierven de muizen. De muizen in de controlegroep waren daarvoor al lang dood gegaan aan de tumoren.
Het medicijn slaat alleen aan bij die tumoren die een bepaald gen P16 missen in combinatie met bepaalde moleculen, de cycline-afhankelijke kinasen 4 en 6 (CDK4 / 6),of waarbij dit gen weinig aanwezig is. De status van dit gen in combinatie met CDK4 / 6, is gemakkelijk vooraf aan de behandeling vast te stellen aldus de onderzoekers. De wetenschappers zeggen ook dat zij dit medicijn nu onderzoeken en uitproberen bij dieren ingespoten met tumoren van Kahler - multiple myeloma en borstkanker.
Hier een bericht over dit medicijn van clinical trials:
Cancer Res. 2010 Apr 15;70(8):3228-38. Epub 2010 Mar 30.
Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts.
Michaud K, Solomon DA, Oermann E, Kim JS, Zhong WZ, Prados MD, Ozawa T, James CD, Waldman T.
Department of Neurological Surgery, Helen Diller Comprehensive Cancer Center, University of California San Francisco, California 94143-0520, USA.
Abstract
Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study, we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6-specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G(1) cell cycle arrest and induction of senescence in each of 16 retinoblastoma protein (Rb)-proficient cell lines regardless of other genetic lesions, whereas 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. Short hairpin RNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 died as a result of disease progression while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy. (c) 2010 AACR.
PMID: 20354191 [PubMed - in process]
