SPORE in Breast Cancer

湾区乳腺癌孢子更新应用侧重于两个领域的未满足需求-改善癌前疾病的管理和更有效地治疗对当前治疗策略反应不佳且转移风险高的侵袭性癌症亚型。我们的方法是基于一个日益完善的概念，即乳腺癌是一种异质性疾病，其中分子定义的亚群进展和对治疗的反应不同。本续期申请中提出的工作将在四个项目中进行：项目1 - DCIS女性后续肿瘤的风险分层将验证在最后一个项目期间发现的在早期乳腺癌发展中重要的分子事件将与DCIS后续进展为浸润性癌症的风险相关的假设。项目2 -乳腺癌亚群识别和治疗的基因组方法将识别FDA批准的和实验药物，这些药物对基础和腔内/放大型乳腺癌亚型有效，开发分子标记分析来指导这些药物的临床应用，并探索有效药物运作的分子机制。项目3 -基于纳米颗粒的侵袭性乳腺癌亚型化疗将开发基于脂质纳米颗粒的免疫靶向治疗侵袭性乳腺癌表型，特别强调治疗基底样肿瘤。项目4 -基于端粒酶功能失调的乳腺癌治疗药物将继续开发一种核酸构建物，以敲低内源性人类端粒酶RNA （siRNA对抗hTer）的表达，并引入突变模板hTer (MT-hTer)，迫使突变端粒合成，从而诱导快速的DMA损伤反应，端粒脱帽和细胞凋亡。这些项目将由管理、组织和结果、生物统计学、生物信息学核心提供支持。此外，倡导核心将相关的患者经验注入SPORE，解决转化研究的经常性障碍，并与湾区和全国各地的各种组织建立网络。

The Bay Area Breast Cancer SPORE renewal application focuses on unmet needs in two areas - improved management of premalignant disease and more effective treatment of invasive cancer subtypes that do not respond well to current therapeutic strategies and that are at high risk of metastasis. Our approach is based on the increasingly well-established concept that breast cancer is a heterogeneous disease in which molecularly defined subsets progress and respond differentially to therapy. Work proposed in this renewal application will be carried out in four projects: Project 1 - Risk Stratification for Subsequent Tumors in Women with DCIS will test the hypothesis that the molecular events discovered to be important in early breast cancer development during the last project period will be associated with risk of subsequent progression of DCIS to invasive cancer. Project 2 - Genomic Approaches to Breast Cancer Subsets Identification and Treatment will identify FDA approved and experimental drugs that are effective against basal and luminal/amplifier breast cancer subtypes, develop molecular marker assays to guide the clinical introduction of these drugs and explore the molecular mechanisms through which effective drugs operate. Project 3 - Nanoparticle-based Chemotherapy against Aggressive Breast Cancer Subtypes will develop lipidic nanoparticle-based therapies immunologically targeted to aggressive breast cancer phenotypes, with particular emphasis on treatment of basal-like tumors. Project 4 - Breast Cancer Therapeutic Agents Based on Telomerase Misfunction will continue to develop a nucleic acid construct to knock down expression of endogenous human telomerase RNA (siRNA against hTer) and introduce mutant-template hTer (MT-hTer) to force synthesis of mutant telomeres thereby inducing a rapid DMA damage response with telomere uncapping and apoptosis. These projects will supported by cores for Administration, Tissue and Outcomes, Biostatistics, Bioinformatics. In addition, an Advocacy Core infuses relevant patient experiences into the SPORE, addresses recurrent barriers to translational research, and networks with various organizations throughout the Bay Area and nationally.