Cancer research communications最新文献

{"title":"ClinVar Database Evolution and Impact on Potential Pathogenic Germline Variant Reporting from Tumor Comprehensive Genomic Profiling.","authors":"Allison W Kurian, Erica Gornstein, Lisa Heppler, Kali Chatham Dougherty, Rachel B Keller-Evans","doi":"10.1158/2767-9764.CRC-25-0038","DOIUrl":"10.1158/2767-9764.CRC-25-0038","url":null,"abstract":"<p><p>Although recommended for a high percentage of patients with cancer, germline genetic testing is widely underutilized. Classification of pathogenic variants of potential germline origin (potential pathogenic germline variants; PPGV) from tumor comprehensive genomic profiling enables identification of patients and families with high cancer risk via an alternative pathway to clinical germline evaluation. Foundation Medicine utilizes evidence in the ClinVar database to classify PPGVs. We investigated the impact of ClinVar database evolution over a 2-year period on the classification of PPGVs across solid tumors. Substantial growth in the database (a 52.2% increase in classified variants across 24 cancer susceptibility genes) yielded a modest increase in PPGV prevalence (+0.5% across tissue and liquid biopsies combined). Whereas filtering of PPGVs because of insufficient evidence for pathogenic classification decreased across all ancestry groups, disproportionate filtering of variants in patients of South Asian (40.0%), admixed American (36.5%), and African (36.3%) versus European genomic ancestry (33.8%, P ≤ 0.01 for all comparisons) was still observed. Continuing improvements to genetic testing access and data sharing are needed to mitigate disparities.</p><p><strong>Significance: </strong>Whereas efforts to improve data sharing have led to the growth of public genomic databases (e.g., ClinVar) over time, underutilization of genetic testing and persistent racial and ethnic disparities are limitations that continue to affect these important resources.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1282-1287"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct Co-Targeting of Bcl-xL and Mcl-1 Exhibits Synergistic Effects in AR-V7-Expressing CRPC Models.","authors":"Benjamin C Brim, Andres F Leon, Erica L Beatson, Jessica D Kindrick, Kinjal Bhadresha, Xiaohu Zhang, Giulia C Napoli, Emily N Risdon, Keith T Schmidt, Kelli M Wilson, Crystal McKnight, Erin Beck, Carleen Klumpp-Thomas, Michele Ceribelli, JuanJuan Yin, Adam G Sowalsky, Douglas K Price, Cindy H Chau, Craig J Thomas, William D Figg","doi":"10.1158/2767-9764.CRC-25-0096","DOIUrl":"10.1158/2767-9764.CRC-25-0096","url":null,"abstract":"<p><p>There is an unmet need to develop novel treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC). Patients often develop resistance to next-generation hormonal therapies that target the androgen receptor (AR) axis (e.g., abiraterone and enzalutamide). A splice variant of AR, AR-V7, is associated with resistance to these inhibitors as well as mCRPC progression and poor prognoses. We embarked upon a high-throughput screen to identify synergistic combinations of targeted therapies using two CRPC cell lines, LNCaP95 and VCaP-CR. Combinations targeting BCL2L1 (Bcl-xL) (A-1331852 and navitoclax) and MCL1 (S63845) synergistically decreased cell viability and induced apoptotic activity via cleavage of PARP, caspase 3, and caspase 7 across AR-V7-expressing CRPC cell lines (LNCaP95, VCaP-CR, and 22Rv1) and a patient-derived organoid model (LuCaP 167CR). We also explored the use of a Bcl-xL-specific proteolysis-targeting chimera degrader (PROTAC) to minimize platelet toxicity associated with Bcl-xL inhibitors. We showed similar synergistic efficacy with the Bcl-xL-targeting PROTAC in combination with S63845 in the three-dimensional spheroid models. Our findings support further preclinical development of Bcl-xL and Mcl-1 inhibitors for mCRPC.</p><p><strong>Significance: </strong>Using an unbiased, combinatorial, high-throughput drug screen, we identified the combination of co-targeting Bcl-xL and Mcl-1 to be highly synergistic across AR-V7-expressing CRPC models. We showed efficacy in higher-order models through validation across in vitro models spanning two-dimensional cell culture, three-dimensional cell culture, and a patient-derived organoid model. These findings identify a promising therapeutic strategy for patients with AR-V7-expressing CRPC.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1396-1408"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12368576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemoimmunotherapy Outcomes and Prognostic Factors in Patients with Advanced, Low PD-L1-Expressing Non-Small Cell Lung Cancer.","authors":"Tae Hata, Tadaaki Yamada, Yasuhiro Goto, Akihiko Amano, Yoshiki Negi, Satoshi Watanabe, Naoki Furuya, Tomohiro Oba, Tatsuki Ikoma, Akira Nakao, Keiko Tanimura, Hirokazu Taniguchi, Akihiro Yoshimura, Tomoya Fukui, Daiki Murata, Kyoichi Kaira, Shinsuke Shiotsu, Makoto Hibino, Asuka Okada, Yusuke Chihara, Hayato Kawachi, Takashi Kijima, Koichi Takayama","doi":"10.1158/2767-9764.CRC-25-0157","DOIUrl":"10.1158/2767-9764.CRC-25-0157","url":null,"abstract":"<p><p>Chemoimmunotherapy is recommended for patients with non-small cell lung cancer (NSCLC) with low PD-L1 expression, but the effect of additional immunotherapy is heterogeneous in this population. To identify patients who do not benefit from the addition of immune checkpoint inhibitors (ICI) to chemotherapy, we conducted a retrospective study at 19 institutions in Japan. We analyzed 851 patients with advanced NSCLC with a PD-L1 tumor proportion score of 1% to 49% who received chemoimmunotherapy (n = 504) or chemotherapy (n = 347) between March 2017 and June 2022. After adjustment by propensity score matching, the median overall survival (OS) was 22.3 months in the chemoimmunotherapy group and 17.0 months in the chemotherapy-alone group (P = 0.01). Multivariate analysis showed that among 12 clinical factors, liver metastases (P = 0.001) and history of antibiotic use (P = 0.02) were independently associated with shorter OS in the chemoimmunotherapy group. Patients with liver metastases (OS, P = 0.4; progression-free survival, P = 0.06) or history of antimicrobial use (OS, P = 0.24; progression-free survival, P = 0.09) did not benefit from the addition of ICI to chemotherapy. Patients with a history of antimicrobial use experienced more severe pneumonitis with chemoimmunotherapy than all patients (P = 0.04). This cohort study showed that liver metastases and prior antimicrobial therapy are the most important clinical factors that attenuate the efficacy of chemoimmunotherapy in patients with low PD-L1 expression.</p><p><strong>Significance: </strong>This study shows that liver metastases and prior antibiotic use are key factors for chemoimmunotherapy in advanced NSCLC cases with low PD-L1 expression. They reduce the benefit of adding ICIs to chemotherapy, underscoring the need for new strategies to improve ICI efficacy in patients.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1203-1214"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12284348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling High-Risk Pediatric Cancers in Zebrafish to Inform Precision Therapy.","authors":"Nadine Azzam, Jamie I Fletcher, Nicole Melong, Loretta M S Lau, Emmy M Dolman, Jie Mao, Gabor Tax, Roxanne Cadiz, Lissandra Tuzi, Alvin Kamili, Biljana Dumevska, Jinhan Xie, Jennifer A Chan, Donna L Senger, Stephanie A Grover, David Malkin, Michelle Haber, Jason N Berman","doi":"10.1158/2767-9764.CRC-25-0080","DOIUrl":"10.1158/2767-9764.CRC-25-0080","url":null,"abstract":"<p><p>Despite advances in precision medicine, 30% of high-risk pediatric cancers lack an actionable molecular target, hindering effective treatment and affecting survival outcomes. Although mouse patient-derived xenograft (PDX) models offer additional insights into clinical drug responses, delivering findings from these models within a clinically actionable time frame remains challenging. This international collaboration between two national precision medicine programs demonstrates proof-of-principle that individualized larval zebrafish PDXs can robustly and rapidly assess clinical responses in high-risk pediatric cancers. Retrospective zebrafish PDX testing was performed on tumor samples from 10 pediatric patients with high-risk cancers. Drug responses in zebrafish models were correlated with clinical responses for each patient and directly compared with responses in cognate mouse PDX models. Responses to conventional and targeted therapies, administered as single agents or in combinations, were assessed. Zebrafish PDXs were successfully established from all 10 patients and provided robust drug response data in every case, including from three patients whose tumor samples could not be engrafted in mice. Remarkably, zebrafish models accurately recapitulated patient responses for 11 of 12 treatment regimens. These findings highlight the potential of larval zebrafish PDX models to provide real-time, clinically relevant drug response data, supporting their potential use in prospective precision medicine studies.</p><p><strong>Significance: </strong>This proof-of-principle study is the first to compare drug responses in larval zebrafish and mouse PDX models with patient outcomes in pediatric precision oncology, showing high concordance. Results highlight the potential of zebrafish PDX models to predict drug responses in high-risk cancers more accurately, rapidly, and cost-effectively in prospective studies.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1215-1227"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12290838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Racial Disparities in Analgesic and Psychiatric Medication Use During End-Of-Life Care in Advanced-Stage Colorectal Cancer: A Retrospective Cohort Study.","authors":"John M Allen, Olga M Trejos Kweyete, Yi Guo, Jiang Bian, Xiwei Lou, Sherise C Rogers, Lisa Scarton, David L DeRemer, Diana J Wilkie","doi":"10.1158/2767-9764.CRC-25-0164","DOIUrl":"10.1158/2767-9764.CRC-25-0164","url":null,"abstract":"<p><p>This study examined racial and ethnic disparities in the use of analgesic and psychiatric medications during end-of-life care among Medicare beneficiaries with advanced-stage colorectal cancer. Using the Surveillance, Epidemiology, and End Results-Medicare-linked database from 2005 to 2017, we identified 28,212 patients with stage IV colorectal cancer who died within 1 year of diagnosis. Multivariable logistic regression models were used to assess differences in medication use by race and ethnicity. Compared with non-Hispanic White patients, Black patients had significantly lower odds of opioid use [adjusted OR (aOR) = 0.86; 95% confidence interval (CI), 0.80-0.93] and overall analgesic use, whereas Hispanic patients had higher use of opioids (aOR = 1.12; 95% CI, 1.03-1.22) and non-opioid analgesics (aOR = 1.22; 95% CI, 1.06-1.40). Asian patients had increased non-opioid use (aOR = 1.71; 95% CI, 1.44-2.03) and decreased skeletal muscle relaxant use (aOR = 0.59; 95% CI, 0.43-0.82). Across all minority groups, psychiatric medication use was consistently lower than in non-Hispanic White patients. These disparities persisted after adjusting for demographic, clinical, and socioeconomic factors. Findings highlight the urgent need for equitable, culturally responsive symptom management strategies to improve the quality of end-of-life care in this population.</p><p><strong>Significance: </strong>We identified significant disparities in the use of analgesic and psychiatric medications among patients with advanced-stage colorectal cancer. Our findings are significant given the emerging importance of symptom management on health-related quality of life and survival. Future research is needed to understand causal factors, their influence on patient-reported outcomes such as symptom relief, and the development of strategies to close these medication use gaps.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1095-1101"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Ancestry, Intrinsic Tumor Subtypes, and Breast Cancer Survival in Latin American Women.","authors":"Daniela Alves da Quinta, Darío Rocha, Cristian Yáñez, Renata Binato, Sheila Coelho Soares-Lima, Xiaosong Huang, Daiana Ganiewich, Valentina A Zavala, Monica Sans, Alejandra Lopez-Vazquez, Jael Quintero, Olivia Valenzuela, Antonio Quintero-Ramos, Alicia Del Toro-Arreola, Mauricio Cerda, Katherine Marcelain, Susanne Crocamo, Maria Aparecida Nagai, Dirce M Carraro, Marcia Maria Chiquitelli Marques, Jorge Gómez, Nora Artagaveytia, Adrian Daneri-Navarro, Bettina G Müller, Javier Retamales, Carlos Velazquez, Elmer A Fernández, Osvaldo L Podhajcer, Eliana Abdelhay, Ricardo A Verdugo, Andrea S Llera, Laura Fejerman","doi":"10.1158/2767-9764.CRC-25-0014","DOIUrl":"10.1158/2767-9764.CRC-25-0014","url":null,"abstract":"<p><p>This study investigates the relationship between genetic ancestry, breast cancer subtypes, and survival outcomes among 951 locally advanced breast cancer cases from Argentina, Brazil, Chile, Mexico, and Uruguay, participating in the Molecular Profile of Breast Cancer Study. Array-based genotyping and ADMIXTURE analysis were used for genetic ancestry evaluation. Breast cancer subtypes were defined by IHC and the gene expression-based PAM50 algorithm. The distribution of genetic ancestry, including European, Indigenous American (IA), African (AFR), and East Asian components, revealed a heterogeneous genetic admixture across countries, with the highest IA ancestry observed in Chile (30.9%) and Mexico (30.8%). Testing the relationship between genetic ancestry and breast cancer subtypes demonstrated that a 10% increase in European ancestry was significantly associated with a 14% decrease in the odds of developing HER2-enriched breast cancer, after adjustment by age, nodal status, and the AFR component (adj. P = 0.021, luminal A as reference). Accordingly, a 10% increase in IA ancestry was associated with a 21% increase in the probability of having HER2-enriched breast cancer (adj. P = 0.022). IA ancestry also significantly increased overall survival after adjustment by age, nodal status, and AFR ancestry, although this result is controversial and may be affected by the size and heterogeneity of the Molecular Profile Breast Cancer Study cohort. Our research confirms previous findings of a high prevalence of HER2-dependent breast tumors among Hispanic/Latina women and strengthens the hypotheses of the existence of either population-specific genetic variant(s) or of other ancestry-correlated factors that impact HER2 expression in breast cancer consistently across different Latin American regions.</p><p><strong>Significance: </strong>The evidence in this work supports the idea that factors linked to genetic ancestry influence the prevalence of breast cancer subtypes in Latin America, potentially affecting treatment needs in the region.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1070-1081"},"PeriodicalIF":2.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering Novel lncRNAs Linked to Melanoma Growth and Migration with CRISPR Inhibition Screening.","authors":"Stavroula Petroulia, Kathryn Hockemeyer, Shashank Tiwari, Pietro Berico, Sama Shamloo, Seyedeh Elnaz Banijamali, Eleazar Vega-Saenz de Miera, Yixiao Gong, Palaniraja Thandapani, Eric Wang, Jeffrey L Schloßhauer, Aristotelis Tsirigos, Iman Osman, Ioannis Aifantis, Jochen Imig","doi":"10.1158/2767-9764.CRC-24-0416","DOIUrl":"10.1158/2767-9764.CRC-24-0416","url":null,"abstract":"<p><p>Melanoma being one of the most common and deadliest skin cancers has been increasing since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. Nowadays, the standard of care of advanced melanoma is resection, followed by immune checkpoint inhibition-based immunotherapy. However, a substantial proportion of patients either do not respond or develop resistance. This underscores a need for novel approaches and therapeutic targets as well as a better understanding of the mechanisms of melanoma pathogenesis. Long noncoding RNAs (lncRNA) comprise a poorly characterized class of functional players and promising targets in promoting malignancy. Certain lncRNAs have been identified to play integral roles in melanoma progression and drug resistance; however, systematic screens to uncover novel functional lncRNAs are scarce. In this study, we profile differentially expressed lncRNAs in patient-derived short-term metastatic cultures and BRAF-MEK inhibition-resistant cells. We conduct a focused growth-related CRISPR inhibition screen of overexpressed lncRNAs, validate, and functionally characterize lncRNA hits with respect to cellular growth, invasive capacities, and apoptosis in vitro as well as the transcriptomic impact of our lead candidate the novel lncRNA XLOC_030781. In sum, we extend the current knowledge of ncRNAs and their potential relevance in melanoma.</p><p><strong>Significance: </strong>LncRNAs have emerged as novel players in regulating many cellular aspects also in melanoma. The number of functional significances of most lncRNAs remains elusive. We provide a comprehensive strategy to identify functionally relevant lncRNAs in melanoma by combining expression profiling with CRISPR inhibition growths screens. Our results broaden the characterized lncRNAs as potential targets for future therapeutic applications.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1102-1118"},"PeriodicalIF":2.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein-Level Analysis of Differential Response to Chemotherapy in Triple-Negative Breast Cancer Identifies CYP1B1 as a Biomarker for Chemotherapy Resistance.","authors":"F Scott Heinemann, Paul D Gershon","doi":"10.1158/2767-9764.CRC-25-0034","DOIUrl":"10.1158/2767-9764.CRC-25-0034","url":null,"abstract":"<p><p>Resistance to chemotherapy is a critical challenge in triple-negative breast cancer (TNBC). In this study, the proteomes of pretreatment core biopsy samples from 16 patients with TNBC with differential response to neoadjuvant chemotherapy (NAC) were analyzed by nanoLC/MS-MS to identify biomarkers of intrinsic chemotherapy resistance. This led to the identification of cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) and 71 additional proteins as significantly more abundant in chemoresistant than chemosensitive TNBC. IHC analysis of 80 TNBC samples confirmed an association between elevated tumor cell CYP1B1 and residual cancer burden class 2/3 disease after NAC in T cell-excluded (TCE) TNBC (P < 0.01) but not in T cell-infiltrated (TCI) TNBC. The frequency of complete pathologic response in TCE-TNBC with elevated CYP1B1 was 18% versus 56% in TCE-TNBC with low CYP1B1 and 75% in TCI-TNBC. Retrospective review of the chemotherapy regimens suggested that TCE-TNBC with elevated CYP1B1 was particularly resistant to doxorubicin/cyclophosphamide. This study is the first to associate resistance to NAC in TNBC with elevated CYP1B1.</p><p><strong>Significance: </strong>This retrospective analysis of pretreatment TNBC core biopsies found that elevation of CYP1B1, a drug-metabolizing enzyme in tumor cells, was associated with resistance to NAC in patients with TNBC treated initially with doxorubicin. If confirmed, this pattern of chemotherapy resistance could guide future clinical trials.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1060-1069"},"PeriodicalIF":2.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Glucocorticoids on Immune Checkpoint Inhibitor Efficacy and Circulating Biomarkers in Non-Small Cell Lung Cancer Patients.","authors":"Lauren Polyakov, Angelina Lim, Alexandra Meyer, Aubree Mades, Joshua Ni, Ryan Cooper, Shirley Ye, Ryutaro Kajihara, Takaaki Oba, Leslie Contreras, Eihab Abdelfatah, Joy Sarkar, Junko Matsuzaki, Ming Li, Rajeev Sharma, Brahm H Segal, Robert C Hsu, Hongbin Chen, Jorge Nieva, Fumito Ito","doi":"10.1158/2767-9764.CRC-25-0051","DOIUrl":"10.1158/2767-9764.CRC-25-0051","url":null,"abstract":"<p><p>Corticosteroids are frequently prescribed to patients with non-small cell lung cancer (NSCLC) for palliation of cancer-related symptoms; however, the potential impact of baseline steroid use on immune checkpoint inhibitor (ICI) therapy and its underlying mechanisms remain unclear. In this study, we evaluated clinical outcomes of 277 patients with NSCLC treated with ICI therapy at two academic institutions. Twenty-one patients (8%) were taking steroids at the start of ICIs. Patients on baseline steroids had a lower overall response rate with markedly shorter progression-free survival and overall survival compared with those not receiving steroids. In multivariate analysis, steroid use was the only significant independent risk factor for disease progression and mortality in both independent cohorts, Roswell Park Comprehensive Cancer Center (n = 88) and University of Southern California (n = 189). A baseline peripheral blood neutrophil-to-lymphocyte ratio <5 was a strong prognostic indicator; however, the prognostic value of neutrophil-to-lymphocyte ratio was absent in patients receiving steroids. Additionally, the baseline frequency of circulating CX3CR1+CD8+ T cells was substantially lower in patients on steroids. Using a bedside-to-bench approach, we found that concurrent steroid use significantly decreased antitumor efficacy of anti-PD-1 therapy and attenuated the increase of CX3CR1+CD8+ T cells in mice bearing MC38 tumors whereas discontinuation of steroid at the start of treatment did not make a negative impact on survival. Collectively, baseline steroid use was associated with worse outcomes and decreased frequency of circulating differentiated effector T cells in patients with NSCLC. Caution should be taken when interpreting the results from circulating immune-related biomarkers in patients on steroids.</p><p><strong>Significance: </strong>The impact of corticosteroids, widely prescribed for palliation of cancer-related symptoms, on ICI therapy remains unclear. This study shows that baseline steroid use is a negative independent prognostic factor in patients with NSCLC undergoing ICI therapy and provides insights into the decreased T-cell effector differentiation and utility of predictive blood-based markers by steroids.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":"5 7","pages":"1082-1094"},"PeriodicalIF":2.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase 1b/2 Study of TP-0903 and Decitabine Targeting Mutant TP53 and/or Complex Karyotype in Patients with Untreated Acute Myeloid Leukemia ≥Age 60 Years.","authors":"Eric D Eisenmann, Ronan Swords, Ying Huang, Shelley Orwick, Daelynn Buelow, Nicole Abbott, Mitch Phelps, Joshua Zeidner, Matthew C Foster, Tara L Lin, Maria R Baer, Yazan F Madanat, Tibor Kovacsovics, Robert Redner, Zeina Al-Mansour, Bhavana Bhatnagar, Mona Stefanos, Molly Martycz, Franchesca Druggan, Timothy L Chen, Ashley O Yocum, Uma Borate, Brian J Druker, Amy Burd, Ross L Levine, John C Byrd, Sharyn D Baker, Alice S Mims","doi":"10.1158/2767-9764.CRC-25-0091","DOIUrl":"10.1158/2767-9764.CRC-25-0091","url":null,"abstract":"<p><strong>Purpose: </strong>Older patients who have acute myeloid leukemia (AML) with mutant TP53 and/or complex karyotype have a dismal prognosis and lack treatment options. Having previously demonstrated that TP-0903, a multikinase inhibitor, has compelling preclinical activity in drug-resistant AML, including TP53-mutated AML, we evaluated the clinical activity of TP-0903 in combination with decitabine.</p><p><strong>Patients and methods: </strong>This was a multicenter, open-label, phase 1b/2 substudy of Beat AML Master Trial (ClinicalTrials.gov: NCT03013998). The phase 1b portion used a 3 + 3 design, and the phase 2 portion used a Simon two-stage design. Eligible patients ages ≥60 years who had newly diagnosed AML with mutations in TP53 and/or complex karyotype (≥3 cytogenetic abnormalities) received either 37 mg (group 1) or 25 mg (group 2) TP-0903 orally on days 1 to 21 with decitabine 20 mg/m2 on days 1 to 10 for up to three 28-day induction cycles, followed by up to 30 maintenance cycles in which decitabine dosing was reduced to days 1 to 5. The primary endpoint was complete remission (CR) by the end of six cycles of treatment.</p><p><strong>Results: </strong>The overall composite remission rate (CR/CR with incomplete count recovery/CR with hematologic improvement) was 33.3% in group 1 and 50.0% in group 2, with CR rates of 13.3% and 25%, respectively. The median overall survival for groups 1 and 2 was 7.6 and 7.5 months, respectively.</p><p><strong>Conclusions: </strong>The combination of TP-0903 and decitabine was reasonably tolerated and had activity in this patient population. Further research and novel treatment strategies are necessary to improve outcomes for patients with these high-risk subtypes of AML.</p><p><strong>Significance: </strong>Treatment options for AML with mutant TP53 and/or complex karyotype are limited. In a phase 1b/2 clinical trial, TP-0903, a multikinase inhibitor, was well-tolerated and had activity comparable with other emerging therapies. Our results suggest that TP-0903 may offer insight and serve as a benchmark for the development of future agents leveraging similar strategies or scaffolds to improve outcomes in these intractable subtypes of AML.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1129-1139"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}