Saskia Brachmann, PhD
(Co-Mentor: Stephane Ferretti, MSc)
The PI3K pathway is one of the most commonly mutated pathways in human cancer. Tumor suppressor mutations in PTEN and activating mutations in PI3K lead to constitutive pathway activation. As such, numerous clinical therapeutics have been developed against distinct nodes of this pivotal pathway. Many of these inhibitors have entered the clinic and thus far have shown the most robust efficacy in the breast cancer setting. However, even here, combination treatments targeting other genetic alterations or driver pathways are necessary to achieve robust responses. Eventually most patients develop therapeutic resistance and disease progression. Recent advances in the application of NGS-based sequencing to tumor sub-populations has revealed that many human tumors are composed of multiple mutated clonal populations that appear to evolve in parallel and gain distinct patterns of genetic co-alterations leading to intra-tumoral heterogeneity (ITH). This ITH offers additional fexibility to adapt to changing environments and therefore likely fosters cancer metastasis and treatment resistance. Since the mechanisms that drive or maintain disease progression are poorly understood, investigating such mechanisms should provide insight into how to therapeutically target the resistant primary tumors or metastases.
To begin to address the problem of intratumoral heterogenity and to study the role played by ITH in resistance and metastases, we are trying to develop preclinical models that recapitulate this ITH. We are using a combination of genomic, proteomic, and functional RNAi approaches in order to gain insight into how to tackle cancer progression therapeutically despite this observed ITH.
Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials.
Fritsch C, Huang A, Chatenay-Rivauday C, Schnell C, Reddy A, Liu M, Kauffmann A, Guthy D, Erdmann D, De Pover A, Furet P, Gao H, Ferretti S, Wang Y, Trappe J, Brachmann SM, Maira SM, Wilson C, Boehm M, Garcia-Echeverria C, Chene P, Wiesmann M, Cozens R, Lehar J, Schlegel R, Caravatti G, Hofmann F, Sellers WR.
Mol Cancer Ther. 2014 May;13(5):1117-29. doi: 10.1158/1535-7163.MCT-13-0865. Epub 2014 Mar 7.
Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations.
Brachmann SM, Kleylein-Sohn J, Gaulis S, Kauffmann A, Blommers MJ, Kazic-Legueux M, Laborde L, Hattenberger M, Stauffer F, Vaxelaire J, Romanet V, Henry C, Murakami M, Guthy DA, Sterker D, Bergling S, Wilson C, Brümmendorf T, Fritsch C, Garcia-Echeverria C, Sellers WR, Hofmann F, Maira SM.
Mol Cancer Ther. 2012 Aug;11(8):1747-57. doi: 10.1158/1535-7163.MCT-11-1021. Epub 2012 May 31.
Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells.
Brachmann SM, Hofmann I, Schnell C, Fritsch C, Wee S, Lane H, Wang S, Garcia-Echeverria C, Maira SM.
Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22299-304. doi: 10.1073/pnas.0905152106. Epub 2009 Dec 10.
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