Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer

开发针对炎性乳腺癌肿瘤微环境的新疗法

• 批准号: 10390676
• 负责人: Naoto T Ueno
• 金额: $ 53.68万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2022-12-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390676
• 关键词: Animal Cancer Model; Antitumor Response; Breast Cancer Model; Breast Cancer Patient; CCL2 gene; CCL20 gene; CXCL5 gene; Cell Proliferation; Cell Survival; Clinical; Clinical Research; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Data; Development; Epidermal Growth Factor Receptor; Failure; Fc Receptor; Flow Cytometry; Genetic Transcription; Histologic; IL8 gene; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunotherapy; In complete remission; Infiltration; Inflammatory; Malignant Neoplasms; Neoadjuvant Therapy; Pathologic; Pathway interactions; Patients; Phase II Clinical Trials; Phenotype; Receptor Inhibition; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Resistance; Role; Testing; Therapeutic; Tissue Microarray; Tissues; anti-PD-L1 antibodies; anti-cancer; anticancer research; base; breast cancer genomics; chemokine; chemotherapy; clinically relevant; combinatorial; efficacy testing; genomic data; humanized mouse; immune checkpoint; immunoreactivity; in vitro Assay; in vivo; inflammatory breast cancer; macrophage; malignant breast neoplasm; mouse model; neoplastic cell; new therapeutic target; novel; panitumumab; patient response; preclinical study; predicting response; prevent; single-cell RNA sequencing; targeted treatment; therapeutic target; transcription factor; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

PROJECT SUMMARY Despite great promise, immune checkpoint inhibitors (ICIs) have had only modest impact on breast cancer patients’ survival. Mechanistic studies into the interplay between the immune system and the tumor cells identified the tumor microenvironment (TME) as the critical factor in dictating the impact of ICIs on tumor progression. Clinical advancements in ICI efficacy will require combinations with agents that can induce a broad shift in the microenvironmental milieu, which may prove especially important for highly aggressive tumors. Inflammatory breast cancer (IBC) is a rare and highly lethal breast cancer with few therapeutic options. In phase II clinical trial for triple-negative IBC patients, we found that anti-EGFR antibody panitumumab (PmAb) combined with preoperative chemotherapy led to a high treatment response. We further found that in IBC models, PmAb reduced the expression of immunosuppressive chemokines and led to increased infiltration of cytotoxic T cells; suggesting a broad shift from an immunosuppressive to immunoreactive TME. Building on these preliminary findings, we propose to determine the mechanism by which EGFR promotes the expression of immunosuppressive chemokines and if, in turn, this effect is responsible for the observed immunosuppressive TME in IBC. While EGFR inhibition has been examined as a way to target tumor cell proliferation and survival, to our knowledge, no other group has examined EGFR as a modulator of the TME in IBC. We propose 3 aims: Aim 1: Determine the mechanism by which the EGFR pathway modulates the TME in IBC. We hypothesize that the EGFR pathway induces an immunosuppressive TME in IBC through EGR1-regulated expression of immunosuppressive chemokines. We will test this hypothesis via in vitro assays and our novel humanized IBC immunocompetent mouse model. Aim 2: Evaluate the combination of immunotherapy with EGFR inhibition in IBC. We hypothesize that EGFR-targeted therapy will enhance the efficacy of immunotherapy in IBC by shifting the TME from an immunosuppressive to an immunoreactive phenotype. We will test the efficacy of targeting EGFR and inhibiting immune checkpoints in combination using the novel IBC humanized mouse model and triple-negative breast cancer immunocompetent mouse models with intrinsic and acquired resistance to ICIs. Aim 3: Determine the clinical relevance of EGFR-modulated TME changes in IBC. We hypothesize that reduced expression of EGR1 and its likely transcriptional targets correlates with TME immunoreactive status and predicts IBC patient response to PmAb-based therapies. We will assess the clinical relevance of our pathway using an IBC genomic dataset and multiplexed immunostaining on an IBC tissue microarray and IBC tissues from an ongoing PmAb clinical trial. Upon completion, we expect to identify TME changes that predict patient response to EGFR-targeted therapy and establish a novel EGFR-based combination therapy with ICIs for patients with IBC. Beyond IBC, our research will broaden our understanding of how we can modulate the TME as a potential therapeutic approach.

项目总结