Purpose: We conducted a phase II randomized noncomparative window of opportunity (WOO) trial to evaluate the inhibition of cellular proliferation and the modulation of immune microenvironment after treatment with olaparib alone or in combination with cisplatin or durvalumab in patients with operable head and neck squamous cell carcinoma (HNSCC).
Experimental Design: Forty-one patients with HNSCC were randomized to cisplatin plus olaparib (arm A), olaparib alone (arm B), no treatment (arm C) or durvalumab plus olaparib (arm D). The primary endpoint was to evaluate the percentage of patients in each arm that achieved a reduction of at least 25% in Ki67. Secondary endpoints included objective response rate (ORR), safety, and pathologic complete response (pCR) rate. Paired baseline and resection tumor biopsies and blood samples were evaluated for prespecified biomarkers.
Results: A decrease in Ki67 of at least 25% was observed in 44.8% of treated patients, as measured by quantitative immunofluorescence. The ORR among treated patients was 12.1%. pCR was observed in 2 patients. Two serious adverse events occurred in 2 patients.Programmed death ligand 1 (PD-L1) levels [combined positive score (CPS)] were significantly higher after treatment in arms A and D. Expression of and colony-stimulating factor 1 receptor () genes, markers of M2 macrophages, increased significantly posttreatment whereas the expression of , a marker of M1 macrophages, decreased.
Conclusion: Preoperative olaparib with cisplatin or alone or with durvalumab was safe in the preoperative setting and led to decrease in Ki67 of at least 25% in 44.8% of treated patients. Olaparib-based treatment modulates the tumor microenvironment leading to upregulation of PD-L1 and induction of protumor features of macrophages.
Significance: HNSCC is characterized by defective DNA repair pathways and immunosuppressive tumor microenvironment. PARP inhibitors, which promote DNA damage and "reset" the inflammatory tumor microenvironment, can establish an effective antitumor response. This phase II WOO trial in HNSCC demonstrated the immunomodulatory effects of PARP inhibitor-induced DNA damage. In this chemo-naïve population, PARP inhibitor-based treatment, reduced tumor cell proliferation and modulated tumor microenvironment. After olaparib upregulation of PD-L1 and macrophages, suggests that combinatorial treatment might be beneficial.
Synopsis: Our WOO study demonstrates that preoperative olaparib results in a reduction in Ki67, upregulation of PD-L1 CPS, and induction of protumor features of macrophages in HNSCC.
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http://dx.doi.org/10.1158/2767-9764.CRC-23-0051 | DOI Listing |
Gut Microbes
December 2025
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
The intracellular bacterium (Fn) mediates tumorigenesis and progression in colorectal cancer (CRC). However, the origin of intratumoral Fn and the role of Fn-infected immunocytes in the tumor microenvironment remain unclear. Here, we observed that Fn-infected neutrophils/macrophages (PMNs/MΦs), especially PMNs, accumulate in tumor tissues and fecal Fn abundance correlates positively with an abundance of blood PD-L1 PMNs in CRC patients.
View Article and Find Full Text PDFActa Biomater
December 2024
Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Changsha, China. Electronic address:
Osteosarcoma tissues demonstrated elevated expression of proteins (FDX1 and DLAT) integral to cuproptosis in our preliminary study, indicating the potential effectiveness of anti-tumor strategies predicated on this process. Nevertheless, the overexpression of copper export proteins and the challenge of copper ion penetration may contribute to insufficient local copper ion concentration for inducing cuproptosis. Herein, we engineered a biomimetic copper-elesclomol-polyphenol network for the efficient delivery of copper ions and the copper ionophore elesclomol.
View Article and Find Full Text PDFJ Ethnopharmacol
December 2024
School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China. Electronic address:
Ethnopharmacological Relevance: Lichong decoction (LD) is extensively employed in the treatment of uterine leiomyoma (ULM), demonstrating remarkable clinical effectiveness with an absence of notable adverse reactions. Its composition aligns with the traditional Chinese medicine (TCM) etiology of ULM, making it a highly suitable therapy. Nonetheless, the precise mechanisms underlying its therapeutic actions remain to be fully elucidated.
View Article and Find Full Text PDFCell Signal
December 2024
Department of Maxillofacial and Otorhinolaryngology Oncology and Department of Head and Neck Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China. Electronic address:
Nerves are often overlooked as key components of the tumor microenvironment. However, the molecular mechanisms underlying the reciprocal interactions between tumors and nerves remain largely unknown. In this study, we analyzed data from The Cancer Genome Atlas (TCGA) and identified a significant association between DKK1 expression and poor prognosis, as well as a correlation between DKK1 expression and myeloid-derived suppressor cell (MDSC) infiltration in head and neck squamous cell carcinoma (HNSCC) and pancreatic ductal adenocarcinoma (PDAC), two cancer types characterized by pronounced tumor-nerve interactions.
View Article and Find Full Text PDFInt J Biol Macromol
December 2024
State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China; Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, China; College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China. Electronic address:
Salvia miltiorrhiza, the anticancer properties of these components are multifaceted, encompassing the inhibition of tumor growth, prevention of the metastatic spread of cancer cells, enhancement of the sensitivity of cancer cells to chemotherapy and radiation therapy, and the suppression of angiogenesis, which is crucial for tumor growth and survival. In the context of our recent study, we have discovered that tanshinone I, one of the active components of Salvia miltiorrhiza, possesses the ability to inhibit the proliferation of ovarian cancer cells, both in laboratory settings and within living organisms. To further understand the molecular mechanisms behind this effect, we conducted a comprehensive transcriptomic analysis.
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