Regulation of the tumor microenvironment by DNA damage repair proteins
DNA损伤修复蛋白调节肿瘤微环境
基本信息
- 批准号:10998271
- 负责人:
- 金额:$ 18.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-14 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
PROJECT SUMMARY
Background ER+ breast cancer accounts for 2/3 of invasive breast cancer cases diagnosed in the world today. In
patients, ~12% of ER+ tumors have complete loss of MLH1, a tumor suppressor and mismatch repair protein.
We previously showed that MLH1 loss in ER+ breast cancer cells activates HER2 to induce resistance to standard
endocrine therapy. However, the underlying mechanism remains unknown. Preliminary data support a role for
MLH1 loss in altering secretion of HER ligands to mediate HER2 activation. This is of particular interest because
an additional 14% of ER+ patient tumors have heterogeneous loss of MLH1. Although the functional consequence
of heterogeneous MLH1 loss is as yet unknown, a role for MLH1 loss in altering the cancer secretome suggests
a potentially significant impact on bulk tumor phenotypes.
Hypothesis Based on our published work and preliminary data, the proposed study will test the hypothesis that
MLH1 loss in ER+ breast cancer induces secretion of HER ligands, by co-opting cGAS-STING signaling, to
promote HER2-dependent growth of both MLH1– and MLH1+ cells in heterogeneously MLH1– tumors.
Specific Aims Aim 1 will test whether the secretion of HER ligands induced by MLH1 loss mediates HER2
activation to promote endocrine therapy resistance. Here, we will use both in vitro and in vivo approaches to
determine whether the ligands secreted by MLH1- ER+ breast cancer cells promote HER2 heterodimerization
and consequent activation, and thereby endocrine therapy resistant growth. Aim 2 will investigate the mechanism
linking MLH1 loss to HER ligand secretion. Specifically, we will test whether inefficient DNA damage repair in
the absence of MLH1 triggers the cGAS-STING secretory pathway. We will also determine how cGAS-STING
activation promotes HER ligand secretion. Aim 3 will examine the therapeutic impact of heterogeneous MLH1
loss. Using in vitro and in vivo experimental models established in my lab, we will test whether HER2 activation
in both MLH1+ and MLH1- cells in tumors with heterogeneous MLH1 loss renders these tumors globally
susceptible to HER2 inhibitors. We will also use digital spatial profiling to assess the contribution of the secretome
to signaling patterns and therapeutic response in heterogeneously MLH1- tumors.
Impact The results of this study will present new therapeutic strategies to help >25,000 women diagnosed each
year with ER+ breast cancer characterized by heterogeneous MLH1 loss. Our work will also provide novel insight
into how MLH1 loss modulates the cGAS-STING pathway to promote a pro-growth tumor secretome. Overall,
results from this study will shed new insight into the how MLH1 loss promotes cancer phenotypes.
项目总结
项目成果
期刊论文数量(0)
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Svasti Haricharan其他文献
Svasti Haricharan的其他文献
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{{ truncateString('Svasti Haricharan', 18)}}的其他基金
Regulation of the tumor microenvironment by DNA damage repair proteins
DNA损伤修复蛋白调节肿瘤微环境
- 批准号:
10737565 - 财政年份:2023
- 资助金额:
$ 18.51万 - 项目类别:
A pan-cancer role for MutL loss in inducing treatment resistance
MutL 缺失在诱导治疗抵抗中的泛癌作用
- 批准号:
9583001 - 财政年份:2018
- 资助金额:
$ 18.51万 - 项目类别:
A pan-cancer role for MutL loss in inducing treatment resistance
MutL 缺失在诱导治疗抵抗中的泛癌作用
- 批准号:
9765215 - 财政年份:2018
- 资助金额:
$ 18.51万 - 项目类别:
A pan-cancer role for MutL loss in inducing treatment resistance
MutL 缺失在诱导治疗抵抗中的泛癌作用
- 批准号:
10001982 - 财政年份:2018
- 资助金额:
$ 18.51万 - 项目类别:
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