SPORE in Breast Cancer

旧金山湾区乳腺癌孢子更新应用侧重于两个领域尚未得到满足的需求--改善对癌前疾病的管理，以及对对当前治疗策略反应不佳和转移风险高的浸润性癌症亚型进行更有效的治疗。我们的方法是基于一个日益成熟的概念，即乳腺癌是一种异质性疾病，在这种疾病中，分子定义的亚群进展和对治疗的反应不同。本次续展申请中提议的工作将在四个项目中进行：项目1--DCIS女性患者后续肿瘤的风险分层将测试这样一个假设，即在上一个项目期内发现的在早期乳腺癌发展中重要的分子事件将与DCIS随后发展为浸润性癌症的风险有关。项目2--乳腺癌亚群识别和治疗的基因组方法将确定FDA批准的对基础和腔/放大乳腺癌亚型有效的实验药物，开发分子标记分析来指导这些药物的临床引入，并探索有效药物发挥作用的分子机制。项目3-基于纳米颗粒的化疗治疗侵袭性乳腺癌亚型将开发基于脂质纳米颗粒的疗法，从免疫学上针对侵袭性乳腺癌表型，特别强调治疗基底细胞样瘤。项目4-基于端粒酶功能障碍的乳腺癌治疗药物将继续开发一种核酸结构，以抑制内源性人端粒酶RNA(针对hTer的siRNA)的表达，并引入突变模板hTer(MT-hTer)以迫使突变端粒的合成，从而通过端粒去封顶和细胞凋亡诱导快速的DNA损伤反应。这些项目将得到行政、组织和结果、生物统计学、生物信息学核心的支持。此外，倡导核心将相关的患者经验注入孢子中，解决翻译研究的经常性障碍，并与整个旧金山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.