The journal of targeted therapies in cancer最新文献

{"title":"Abstract IA38: Progress and unanswered questions in EGFR mutation-positive lung cancer","authors":"L. Sequist","doi":"10.1158/1557-3265.AACRIASLC18-IA38","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-IA38","url":null,"abstract":"A summary of the major advances in management of EGFR mutation-positive lung cancer will be provided, along with a discussion of missing pieces of information that could improve the care of patients. Citation Format: Lecia V. Sequist. Progress and unanswered questions in EGFR mutation-positive lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA38.","PeriodicalId":92149,"journal":{"name":"The journal of targeted therapies in cancer","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77010626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B01: BLU-667: A highly selective RET inhibitor to target RET-driven NSCLC","authors":"R. Rahal, Michelle A Maynard, Wei Hu, Jason D. Brubaker, Q. Cao, Joseph L. Kim, M. Sheets, Douglas Wilson, Kevin Wilson, L. DiPietro, T. LaBranche, B. Wolf, T. Guzi, C. Lengauer, E. Evans","doi":"10.1158/1557-3265.aacriaslc18-b01","DOIUrl":"https://doi.org/10.1158/1557-3265.aacriaslc18-b01","url":null,"abstract":"Activating RET fusions have been observed in 1-2% of non-small cell lung adenocarcinomas (NSCLC). These tumors often occur in non-smokers and lack other driver mutations, similar to NSCLC driven by activation of the tyrosine kinases EGFR, ALK or ROS. Multi-kinase inhibitors (mKIs) with in vitro activity against RET, such as cabozantinib and vandetanib, have been tested in RET-rearranged NSCLC, but without the high response rate often seen with targeted therapies in genetically-defined NSCLC, likely a result of off-toxicities that limit the ability to fully inhibit RET kinase activation. BLU-667 is a next-generation kinase inhibitor specifically tailored to target the activated forms of RET, while sparing kinases that contribute to dose-limiting toxicities, such as VEGFR-2. BLU-667 potently inhibited both RET fusion activity (IC50 = 0.4 nM) and demonstrated 88-fold selectivity over VEGFR-2 in enzymatic assays. In a cellular setting, BLU 667 inhibited the most prevalent RET fusion observed in NSCLC, KIF5B-RET, over 20X more potently than the multikinase inhibitors cabozantinib, vandetanib or RXDX-105. KIF5B-RET autophosphorylation and proliferation driven by RET fusions was inhibited with BLU-667 in the low nanomolar range (4 – 15 nM). In vivo oral administration of BLU 667 was well tolerated in mice at all doses and exhibited dose-dependent modulation of oncogenic RET kinase activity in all in vivo models tested, including a KIF5B-RET NSCLC PDX, as well as a KIF5B-RET V804L-driven tumor model with a mutation at the gatekeeper position, a position susceptible to on-target mutation in many oncogenic kinases. Notably, BLU-667, but not cabozantinib, induced tumor growth inhibition without impacting biomarkers of VEGFR-2 inhibition, providing strong evidence that selective inhibition of RET alone is sufficient for antitumor activity in vivo. By sparing off-target kinases with known toxicity profiles, BLU-667 is predicted to robustly inhibit RET at clinically achievable doses. Moreover, with activity against predicted resistance mutations such as those at the gatekeeper position, BLU-667 may prevent or delay the emergence of resistance and therefore provide patients with RET-driven malignancies an opportunity for more durable and effective therapies. As such, BLU-667 is currently in the dose-escalation segment of a first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations (NCT03037385). Citation Format: Rami Rahal, Michelle Maynard, Wei Hu, Jason Brubaker, Qiangfang Cao, Joseph L. Kim, Michael P. Sheets, Douglas P. Wilson, Kevin J. Wilson, Lucian DiPietro, Timothy LaBranche, Beni Wolf, Timothy Guzi, Christoph Lengauer, Erica K. Evans. BLU-667: A highly selective RET inhibitor to target RET-driven NSCLC [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin C","PeriodicalId":92149,"journal":{"name":"The journal of targeted therapies in cancer","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77572587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neoadjuvant Chemotherapy Considerations in Triple-Negative Breast Cancer.","authors":"Nicholas McAndrew,&nbsp;Angela DeMichele","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The optimal neoadjuvant chemotherapy (NACT) regimen in triple-negative breast cancer (TNBC) has not been clearly defined. Achieving a pathologic complete response (pCR) provides important prognostic information, and, especially in TNBC, is considered a surrogate endpoint for event-free survival. Thus, many neoadjuvant studies in TNBC focus on this as a primary endpoint, and such information may be used for accelerated US Food and Drug Administration approval. Current controversies in the field include: (1) the role of platinum-based compounds; (2) the optimal chemotherapy backbone; and (3) the benefits of additional therapy after surgery. Conflicting results of 2 major studies adding carboplatin to NACT have highlighted the need to balance potential benefits to disease outcomes against increased toxicity. While the PROGECT study suggests efficacy of a nonanthracycline-containing regimen, this is observational data, and evidence in the form of a clinical trial remains to be seen. Data surrounding optimal taxane use support the use of nab-paclitaxel in place of paclitaxel in limited clinical situations. Although bevacizumab may increase pCR rates, this has not translated into survival benefit. Capecitabine shows promise in patients who have not achieved pCR after NACT. The neoadjuvant setting remains an important model for drug development. This review will focus on the most important and most current neoadjuvant trials in women with TNBC.</p>","PeriodicalId":92149,"journal":{"name":"The journal of targeted therapies in cancer","volume":"7 1","pages":"52-69"},"PeriodicalIF":0.0,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865448/pdf/nihms943480.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35946404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering Chimeric Antigen Receptor T cells to Treat Glioblastoma.","authors":"Bryan D Choi,&nbsp;Donald M O'Rourke,&nbsp;Marcela V Maus","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Immunotherapy has emerged as a promising strategy for glioblastoma (GBM), a disease that remains universally fatal despite currently available standard-of-care. Adoptive T cell therapy has been shown to produce potent antitumor immunity while obviating the need for traditional antigen presentation and primary immune responses. Chimeric antigen receptors (CARs) are specialized molecules that can be expressed on the surface of T cells allowing for redirected cytotoxicity against tumor antigens of interest. To date, the application of CAR T cells for GBM has been relatively limited, in large part due to a dearth of well-described tumor specific antigens that are both homogenously and frequently expressed. A mutated version of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase that is expressed on the surface of GBM and other common neoplasms, but completely absent from all normal tissues. We have recently generated CAR T cells directed against EGFRvIII and reported results from a Phase I clinical trial investigating this platform in patients with EGFRvIII-expressing GBM. Our study showed that despite conventional notions of central nervous system \"immune-privilege,\" EGFRvIII CAR T cells trafficked to intracerebral tumors, leading to successful targeting and eradication of this antigen in the brain. Here, we review our experience with EGFRvIII CAR T cells and highlight important considerations for the clinical translation of this therapy in patients with GBM.</p>","PeriodicalId":92149,"journal":{"name":"The journal of targeted therapies in cancer","volume":"6 4","pages":"22-25"},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695679/pdf/nihms906268.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35277602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}