The past years have seen tremendous advances in technology that have allowed us to gain powerful insight into the molecular and genetic determinants that drive cancer. However, by comparison, the rate at which this advanced knowledge has been translated into effective therapeutics is pitifully slow. In this proposal, we have designed a novel approach that will complement and streamline the way clinical trials are currently performed. This very novel and exciting initiative is entitled """"""""the Co-Clinical Project"""""""". This venture stems from the realization of the tremendous power of preclinical testing of new drugs, novel drug combinations and novel therapeutic modalities in mouse models of human cancer as has been previously exemplified in the """"""""APL paradigm"""""""". Succinctly put, what we propose with the """"""""Co-Clinical Project"""""""" is that each clinical trial at the participating Institutions will be run """"""""in parallel"""""""" with pre-clinical trials in appropriate, faithful and genetically relevant mouse models, and that the clinical, biological and pharmacological information (i.e. somatic mutational background, germline SNP variations, responsiveness to specific regimens;imaging, microarray and proteomics profiles) will be accrued, analyzed in parallel and integrated in order to facilitate the identification of patient subtypes, key genetic determinants, and biomarkers that predict response to specific treatments. In the proposal, we have chosen to utilize lung cancer and prostate cancer as exemplary models to provide proof of principle to the Co-Clinical project.
The specific aims of this proposal include: 1. The use of genetically engineered mouse models of lung cancer to rapidly predict outcomes of contemporaneous human lung cancer clinical trials. 2. Informing the effectiveness of standard of care and experimental treatments using faithful mouse models of prostate cancer The goal of these aims is to develop and test the efficacy of a """"""""Co-Clinical Project"""""""", in order to dramatically reduce these barriers and design clinical trials that stratify patients on the basis of molecular and genetic criteria, in turn accelerating drug approval. In addition, to accelerate the optimization of combinatorial-targeted therapy on the basis of genetic stratification through the use of GEMs in preclinical trials. We initially propose to develop this novel paradigm towards the study and treatment of cancers where selected informative and faithful models have been already generated. We will expand this paradigm in due course to the analysis and treatment of all forms of cancer.
The """"""""Co-Clinical Trial"""""""" Project was conceived as a new paradigm for the rapid development and subsequent translation of novel cancer therapies from bench to bedside, and vice versa, thereby enabling a more coordinated and coherent effort between basic research and clinical scientists towards the eradication of cancer. This proposal of this application will have a defining impact on how cancer clinical trials are designed and carried out.
|Lunardi, Andrea; Pandolfi, Pier Paolo (2015) A co-clinical platform to accelerate cancer treatment optimization. Trends Mol Med 21:1-5|
|González-Billalabeitia, Enrique; Seitzer, Nina; Song, Su Jung et al. (2014) Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov 4:896-904|
|Lunardi, Andrea; Nardella, Caterina; Clohessy, John G et al. (2014) Of model pets and cancer models: an introduction to mouse models of cancer. Cold Spring Harb Protoc 2014:17-31|
|Hata, Aaron N; Yeo, Alan; Faber, Anthony C et al. (2014) Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and PI3K inhibitors for KRAS-mutant lung cancers. Cancer Res 74:3146-56|
|Lunardi, Andrea; Ala, Ugo; Epping, Mirjam T et al. (2013) A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer. Nat Genet 45:747-55|
|Wang, Guocan; Lunardi, Andrea; Zhang, Jiangwen et al. (2013) Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion. Nat Genet 45:739-746|
|Shimamura, Takeshi; Chen, Zhao; Soucheray, Margaret et al. (2013) Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer. Clin Cancer Res 19:6183-92|
|Chen, Zhao; Cheng, Katherine; Walton, Zandra et al. (2012) A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483:613-7|
|Johnson, Neil; Li, Yu-Chen; Walton, Zandra E et al. (2011) Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nat Med 17:875-82|
|Nardella, Caterina; Lunardi, Andrea; Patnaik, Akash et al. (2011) The APL Paradigm and the ""Co-Clinical Trial"" Project. Cancer Discov 2011:108-116|
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