Therapeutic targeting of autophagy-dependent cancer

自噬依赖性癌症的治疗靶向

• 批准号: 9102009
• 负责人: DANIEL L GUSTAFSON
• 金额: $ 48.26万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9102009
• 关键词: Address; Adjuvant; Adjuvant Chemotherapy; Antineoplastic Agents; Autocrine Communication; Autophagocytosis; Bioinformatics; Breast; Breast Cancer Cell; Breast Cancer cell line; Cancer Biology; Cancer Control; Cancer Patient; Cell Line; Cell Survival; Cells; Cessation of life; Characteristics; Child; Chloroquine; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Conditioned Culture Media; Custom; Data; Dependence; Dependency; Development; Disease Resistance; Gene Expression; Gene Expression Profile; Grant; Health; Human; IL6 gene; Libraries; Malignant Neoplasms; Mammary Neoplasms; Methods; Modeling; Mutate; Mutation; Neoadjuvant Therapy; Neoplasm Metastasis; Paper; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Phenotype; Primary Neoplasm; Process; Regulation; Reporting; Resected; Role; STAT3 gene; Signal Transduction; Signaling Molecule; Specificity; Stem cells; Stress; Testing; Thinking; Tumor Subtype; Work; base; cancer cell; cancer stem cell; cancer subtypes; cancer therapy; cancer type; chemotherapy; clinically relevant; cytokine; improved; in vivo; inhibition of autophagy; inhibitor/antagonist; insight; malignant breast neoplasm; neoplastic cell; novel; novel strategies; research study; response; small hairpin RNA; stem; therapeutic target; therapy resistant; tumor; tumor xenograft

 DESCRIPTION (provided by applicant): Autophagy is important in cancer development, progression and response to therapy. Although we are already trying to target autophagy in the clinic, there is currently no way to identify the tumors that will or will not benefit from autophay inhibition. We recently reported that some breast tumor cells are much more dependent on autophagy than others and our data suggest that it is only in the truly autophagy-dependent tumor cells (which we define as those that require autophagy to survive even in the absence of additional stress) where autophagy inhibition will be effective on its own or in combination with other agents. Indeed, our data suggest that combining autophagy inhibition with another agent in tumor cells that are not autophagy-dependent can be counterproductive. We also identified a potential mechanism to explain autophagy-dependent breast cancer- autophagy controls STAT3 activity in only some tumor cells and this is necessary and sufficient to explain autophagy-dependent survival; moreover recent studies have also indicated that tumor stem-like cell activity requires autophagy in these cells. These data led us to hypothesize: autophagy-dependency defines a specific tumor subtype whose cell survival and stem cell-like characteristics depend on autophagy: these are the tumors that will respond best to autophagy inhibition. To test our hypothesis, we have three specific aims. Aim 1. Identify autophagy-dependent tumors and determine response to autophagy inhibition. We hypothesize that we can identify autophagy-dependent tumors and will test a preliminary gene expression signature that we think can do this. We propose that autophagy inhibition will be effective but only for autophagy-dependent tumors and will test this in primary tumors and by neoadjuvant and adjuvant treatment of surgically resected metastatic tumors. Aim 2. Test if autophagy inhibition sensitizes to other treatments in autophagy-dependent breast cancer. To test the hypothesis that autophagy-dependent tumors will benefit most from combination treatment with autophagy inhibitors, experiments using large scale shRNA analysis well as a novel bioinformatics approach using the COXEN principle will work out how best to target autophagy in combination with other drugs. Aim 3. Determine the mechanism underlying autophagy-dependency in breast tumors. We hypothesize that autophagy regulation of autocrine signaling explains STAT3 activation, survival and stem cell like of autophagy-dependent tumor cells. We will test this by analyzing autophagy's ability to signal through cytokines like IL6, which we have shown is specifically controlled by autophagy only in the autophagy-dependent tumor cells. If our ideas are correct, our work will help define a novel subtype of autophagy-dependent breast cancer and provide a new way to identify, treat and improve combination treatments for these tumors while providing new insights into the roles of autophagy in cancer therapy and cancer biology.

 描述（由申请人提供）：自噬在癌症发生、进展和对治疗的反应中很重要。虽然我们已经在临床上尝试靶向自噬，但目前还没有办法确定哪些肿瘤会或不会从自噬抑制中受益。我们最近报道，一些乳腺肿瘤细胞比其他细胞更依赖于自噬，我们的数据表明，只有在真正的自噬依赖性肿瘤细胞（我们定义为即使在没有额外压力的情况下也需要自噬才能生存的肿瘤细胞）中，自噬抑制本身或与其他药物联合使用才有效。事实上，我们的数据表明，在不依赖自噬的肿瘤细胞中将自噬抑制与另一种药物结合可能会适得其反。我们还确定了一种解释自噬依赖性乳腺癌的潜在机制-自噬仅在某些肿瘤细胞中控制STAT 3活性，这对于解释自噬依赖性生存是必要和充分的;此外，最近的研究还表明，肿瘤干细胞样细胞活性需要这些细胞中的自噬。这些数据使我们假设：自噬依赖性定义了一种特定的肿瘤亚型，其细胞存活和干细胞样特征取决于自噬：这些肿瘤对自噬抑制反应最好。为了验证我们的假设，我们有三个具体目标。目标1.识别自噬依赖性肿瘤并确定对自噬抑制的反应。我们假设我们可以识别自噬依赖性肿瘤，并将测试我们认为可以做到这一点的初步基因表达特征。我们提出自噬抑制将是有效的，但仅适用于自噬依赖性肿瘤，并将在原发性肿瘤中以及通过手术切除的转移性肿瘤的新辅助和辅助治疗来测试这一点。目标2.测试自噬抑制是否对自噬依赖性乳腺癌的其他治疗敏感。为了验证自噬依赖性肿瘤将从与自噬抑制剂的联合治疗中获益最多的假设，使用大规模shRNA分析的实验以及使用COXEN原理的新型生物信息学方法将研究如何最好地与其他药物联合靶向自噬。目标3.确定乳腺肿瘤中自噬依赖的潜在机制。我们推测自噬对自分泌信号的调节解释了自噬依赖性肿瘤细胞的STAT 3激活、存活和干细胞样。我们将通过分析自噬通过细胞因子如IL 6发出信号的能力来测试这一点，我们已经表明，自噬仅在自噬依赖性肿瘤细胞中受到自噬的特异性控制。如果我们的想法是正确的，我们的工作将有助于定义一种新的自噬依赖性乳腺癌亚型，并提供一种新的方法来识别、治疗和改善这些肿瘤的联合治疗，同时为自噬在癌症治疗和癌症生物学中的作用提供新的见解。