Cancer research最新文献

{"title":"Abstract 474: IL-12 immunotherapy using a novel gene delivery platform for RNA payloads achieves effective antitumor responses without systemic toxicity in an aggressive CT26 murine cancer model","authors":"Laura Strauss, Carli Jones Burns, Akihito Inagaki, Stephanie Lees, Noriyuki Kasahara, Cecilia Roh, Robert G. Johnson","doi":"10.1158/1538-7445.am2025-474","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-474","url":null,"abstract":"Background: IL-12 exhibits potent anti-tumor properties, which enhance cytolytic activity and tumor infiltration of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) and activates Th-1-type immune responses [1-2]. However, systemic administration of recombinant IL-12 protein is still a challenge due to serious toxicity resulting from interferon (IFN)-γ overproduction [3-5]. Viral and non-viral vectors for IL-12 gene therapy represent an alternative therapeutic strategy, which can be combined with pro-drug activated cancer killing gene therapy approaches. Combined gene delivery of IL-12 and herpes simplex virus thymidine kinase (HSV-TK) significantly boosts anti-tumor efficacy in animal studies and has been shown to be safe in human clinical studies when administered intratumorally [6-12]. Here we present a novel gene therapy approach for in vivo gene delivery of IL-12 combined with an enhanced gain of function-variant of HSV-TK (v-eTK). Methods: Non-replicating retrovectors encoding murine IL-12 only (mGEN1018, encoding both p35 and p40 subunits, as described previously [13-14], or in combination with v-eTK (mGEN1013), were administered intratumorally or systemically to a subcutaneous tumor model of CT26 murine colorectal cancer in syngeneic BALB/c mice. Mice receiving mGEN1013 were subsequently treated with Ganciclovir (GCV) pro-drug. General health and body weight as well as tumor growth and survival were monitored over time, and immunophenotyping of peripheral blood, spleen, and tumor-infiltrating immune cells was performed. Results: Our data show that in subcutaneous CT26 tumor models, intratumoral and systemic gene delivery of IL-12 by the mGEN1018 vector induces both local and systemic anti-tumor immune responses primarily by stimulating production of IFN-γ from NK cells and CTLs. Gene delivery of IL-12 in combination with v-eTK by the mGEN1013 vector followed by GCV pro-drug showed enhanced tumor growth inhibition and increased survival compared to untreated controls. Systemic anti-tumor effects of IL-12 gene therapy were not associated with visible signs of toxicity or significant body weight loss. Conclusion: Gene delivery of v-eTK followed by GCV treatment results in tumor cell lysis and exposure of tumor antigens, while simultaneously, IL-12 gene delivery enhances anti-tumor immune responses though upregulation of inflammatory cytokines. These results show the potential of mGEN1013 as a novel RNA payload delivery platform for combined GCV pro-drug and more effective tumor-localized IL-12 immunotherapy without systemic toxicity. Citation Format: Laura Strauss, Carli Jones Burns, Akihito Inagaki, Stephanie Lees, Noriyuki Kasahara, Cecilia Roh, Robert G. Johnson. IL-12 immunotherapy using a novel gene delivery platform for RNA payloads achieves effective antitumor responses without systemic toxicity in an aggressive CT26 murine cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeti","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"91 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 833: A novel anti-CEACAM6 heavy-chain antibody-drug conjugate for gastrointestinal cancer therapy","authors":"Ming-Heng Wu, Yao-Tsung Tsai, Chee Voon Yap","doi":"10.1158/1538-7445.am2025-833","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-833","url":null,"abstract":"Antibody-drug conjugates (ADCs) are \"biological missiles\" that utilize a chemical linker to connect monoclonal antibodies (mAbs) with cytotoxic drugs, which induces the precise killing of targeted tumor cells and causes the death of surrounding untargeted cancer cells through the bystander effect. However, current ADCs are too specific to certain cancer subtypes and not specific enough to accurately target a cancer-specific protein, which limits the therapeutic populations and induces unwanted side effects. We developed a heavy-chain antibody (HCAb) from a llama immune library, which recognizes glycosylated CEACAM6 (Carcinoembryonic antigen-related cell adhesion molecule 6), a broad-surface marker of epithelial-type cancers. The anti-CEACAM6 HCAb showed a higher affinity (KD: sub-nanomolar), better thermal stability, unique tissue penetration and epitope-recognition abilities compared to the conventional antibodies. The anti-CEACAM6 HCAb-drug conjugate (HCAb-ADC), which links the HCAb and tubulin inhibitors via hydrophilic linkers, specifically killed CEACAM6-expressing colorectal (CRC), lung, pancreas, and bile duct carcinoma cells at sub-nanomolar concentrations and had a better anti-cancer effect than current FDA-approved ADCs. In xenograft models, a single administration of HCAb-ADC completely abolished colorectal and pancreatic tumors. Notably, HCAb-ADC can effectively inhibit tumor growth even at very low doses (0.2 mg/Kg) and demonstrated a superior therapeutic effect over current therapeutic regimens. Meanwhile, it exhibited minimal toxicity to normal epithelial and peripheral blood mononuclear cells. In summary, the excellent anti-tumor activity across different epithelial cancers and minimal toxicity to normal tissues support the clinical development of the novel HCAb-ADC for treating multiple epithelial-type cancers, including CRC, lung, pancreatic, and bile duct carcinoma. Citation Format: Ming-Heng Wu, Yao-Tsung Tsai, Chee Voon Yap. A novel anti-CEACAM6 heavy-chain antibody-drug conjugate for gastrointestinal cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): nr 833.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"8 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 671: Development of a diagnostic antibody for CD24 targeted therapy","authors":"Peng Chen, Jishun Chen, Min Deng, Rong Guo, Ming Song, Jay Mei, Bing Hou","doi":"10.1158/1538-7445.am2025-671","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-671","url":null,"abstract":"Background: CD24 is a small yet extensively glycosylated glycosylphosphatidylinositol protein that is overexpressed in many tumor cells. Elevated CD24 levels typically indicate a poorer prognosis, as it facilitates malignant activity and confers resistance to chemotherapies. CD24 is also identified as a surface marker of cancer stem cells across multiple tumor types. It triggers an anti-phagocytic by binding to sialic-acid-binding Ig-like lectin 10 (Siglec10) on tumor-associated macrophages, thereby inhibiting the phagocytosis of tumor cells. CD24 has emerged as a promising therapeutic target for anti-cancer treatment. Several clinical trials are being conducted to evaluate the safety and efficacy of CD24-targeted therapies. Here, we developed and characterized an anti-CD24 diagnostic antibody to enhance the screening and selection of patients based on CD24 expression. Methods: SJL mice were immunized with 5-10 million HEK293T-hCD24 cells by intraperitoneal injection. Screening and selection of positive hybridoma clones were conducted using ELISA and flow cytometry analysis. Potential immunohistochemistry (IHC) clones were screened by staining formalin-fixed, paraffin-embedded (FFPE) specimens of human normal esophageal tissue using Leica Bond III platforms. The accuracy assessment, sensitivity (selectivity), specificity, and assay precision were evaluated using the lead antibody. Various human tumor tissue microarrays (TMA), including but not limited to breast cancer, ovarian cancer, urothelial cancer, and small cell lung cancer, were evaluated using lead antibody through IHC staining for further validation. Results: Monoclonal antibody clone ATG1144 binds to the hCD24 core peptide in ELISA with an EC50 of 0.06 nM. Distinct membrane staining on human normal esophageal tissue FFPE specimens can also be observed with IHC staining using ATG1144. For accuracy assessment, six CDX and twenty human specimens, comprising both positive and negative specimens (including solid tumors and B-cell non-Hodgkin lymphomas), were validated. Samples exhibiting high, medium, and low CD24 expression levels were evaluated for sensitivity and specificity, and the interpreted results aligned with the reference outcomes. FFPE tissues from three distinct patients were evaluated for assay precision assessment. The TMA IHC staining result revealed that 50-80% of patients with lung, breast, bladder, ovarian, or liver cancer have CD24 expression on tumor cell surface with low expression in the para-cancerous normal tissue. Conclusion: ATG1144 specifically binds to human CD24 with high sensitivity as demonstrated by IHC staining. The development and validation of the method have been finalized using Leica Bond III platforms. These data suggest a potential diagnostic use of ATG1144 for identifying human CD24 + patients. Citation Format: Peng Chen, Jishun Chen, Min Deng, Rong Guo, Ming Song, Jay Mei, Bing Hou. Development of a diagnostic antibody for CD24 targeted therapy [abst","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"24 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 606: Celastrol treatment induces apoptosis and modulates metabolic pathways in FLT3 - Positive acute myeloid leukemia cells","authors":"Biba Vikas, Vasantharaja Raguraman, Shanid Mohiyuddin, Sofia Vega, Zhentian Lei, Gerhard Hildebrandt, Senthilnathan Palaniyandi","doi":"10.1158/1538-7445.am2025-606","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-606","url":null,"abstract":"Acute Myeloid Leukemia (AML) is a hematologic malignancy with poor prognosis. Historically, its treatment is associated with severe toxicity and mortality. Moreover, the success of chemotherapy is often hampered by drug resistance and relapse, affecting treatment response and long-term survival of patients. To find alternative drugs and targeted immunotherapies for AML remains an unmet need. Celastrol is a natural compound isolated from the medicinal plant Tripterygium wilfordii Hook F. It is a pentacyclic triterpenoid, that has shown therapeutical potential due to its anti-inflammatory and anti-cancer properties, yet the mechanism is poorly understood. In the present study, we demonstrate the cytotoxic effects of celastrol in FLT3 ITD mutated AML. Molecular docking studies confirmed celastrol’s effective binding to the FLT3 protein, suggesting a potential targeted therapy. Cell viability and apoptosis were determined after celastrol treatment in MV-4-11 cells at varying concentrations, and cell viability was hampered in a dose-dependent manner with an IC50 value of 0.3μM. Next, Annexin V and PI staining were used to examine whether this inhibitory effect of celastrol on cell viability was related to the induction of apoptosis. Celastrol-induced cell apoptosis was demonstrated ranging from 75 to 78 % along with increased apoptotic markers like caspase 3, caspase 8, and caspase 9 expression, confirming its ability to trigger the apoptotic cascade through intrinsic and extrinsic pathways. Seahorse assay revealed that celastrol treatment significantly suppressed the maximal oxygen consumption rate (OCR) with minimal effect on basal respiration. Interestingly, combination treatment with celastrol and Giltertinib strongly suppressed maximal OCR. In addition, celastrol treatment affected the extracellular acidification rate (ECAR) in MV-4-11 cells showing a compensatory decrease in glycolysis. Furthermore, untargeted metabolomics showed 18 significantly changed metabolites with better variance between the vehicle and celastrol treatment as evidenced by principal component analysis (PCA). Pathway analysis revealed alterations in glutathione, lipid, and energy metabolism after celastrol treatment. This study demonstrated that celastrol treatment targets both glutathione and glycolysis metabolism which are crucial for cell survival and will potentially be a powerful strategy to induce a more selective, metabolically driven toxicity on FLT3-positive AML cells. The ongoing transcriptomics analysis and the in vivo experiments will delineate celastrol's potential role in treating AML. Citation Format: Biba Vikas, Vasantharaja Raguraman, Shanid Mohiyuddin, Sofia Vega, Zhentian Lei, Gerhard Hildebrandt, Senthilnathan Palaniyandi. Celastrol treatment induces apoptosis and modulates metabolic pathways in FLT3 - Positive acute myeloid leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s);","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"30 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 374: OMX-0407 - A spectrum selective kinase inhibitor shows preclinical efficacy in RCC as well as sarcomas","authors":"Ilona Petra Maser, Carolin Strobl, Bettina Bauer, Andreas Schirmer, Moritz Zulley, Carmen Amerhauser, Marisa Stebegg-Wagner, Tiantom Jarutat, Hannes Loferer, Stefan Bissinger","doi":"10.1158/1538-7445.am2025-374","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-374","url":null,"abstract":"OMX-0407 is an orally available spectrum-selective kinase inhibitor targeting key oncology-relevant tyrosine kinases and the salt-inducible kinase family. OMX-0407 offers a dual mode of action (MoA) in cancer by inducing cell cycle arrest in tumor cells and sensitizing the tumor environment to immune cell-mediated tumor cell killing. It is being developed as first-in-class treatment for solid tumor indications with high unmet medical need. Key oncogenic signaling pathways of tyrosine kinases drive cancer progression by regulating cell cycle and growth signaling cascades. Dysregulation of these kinases, such as platelet-derived growth factor receptors, Eph receptors, and Src family kinases, contributes to cancer progression and therapy resistance. OMX-0407 effectively disrupts these processes through potent inhibition of these kinases and their downstream signaling cascades. A comprehensive viability screen of over 380 human cancer cell lines revealed a selective anti-tumor activity across a subset of cancers, including in renal cell carcinomas (RCC) and sarcomas. Pharmacodynamics studies via phospho-proteomics, Simple-Western or functional kinase activity assays revealed that OMX-0407 induces a G1 cell cycle arrest, accompanied by dose-dependent downregulation of cell cycle-associated proteins and kinase signaling pathways. These effects have been confirmed across in vitro cell line studies, in vivo cell line-derived models or even patient-derived xenograft models. Besides its direct effect on tumor cells, OMX-0407 is repolarizing the tumor microenvironment by reducing immunosuppressive regulatory T cells in the tumor bed and shifting toward a pro-inflammatory state. This dual MoA contributes to the potent anti-tumor effects in various syngeneic animal studies. In a human patient-derived xenograft of epithelioid angiosarcoma (AS), derived from a 9-year-old patient, OMX-0407 demonstrated remarkable dose-dependent anti-tumor efficacy as a single agent. The strong anti-tumor efficacy, with tumor reduction in individual animals, was associated with dose-dependent downregulation of phosphoproteins and significant inactivation of key OMX-0407 regulated signaling pathways on kinase level. Clinical data from a patient, diagnosed with secondary radiation-induced AS, resistant to prior lines of chemotherapy, demonstrated that OMX-0407 was well tolerated and achieved a complete response at doses of up to 60 mg twice daily, which remains ongoing at 14 month. These findings support OMX-0407 as a promising first-in-class therapeutic candidate for the treatment of AS and RCC, with a dual mechanism combining direct anti-tumor effects with repolarization of an immunosuppressive tumor microenvironment. As of September 2024, Ph1b expansion cohorts of the first-in-human trial (NCT05826600) were initiated for patients with unresectable or metastatic AS or clear cell RCC. Citation Format: Ilona Petra Maser, Carolin Strobl, Bettina Bauer, Andreas Schirmer, Moritz Zulle","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"13 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 4972: Changing landscape of liver cancer disparity due to the impact of social determinate of health in Georgia","authors":"Amit Kumar Srivastav, Manoj Kumar Mishra, Shailesh Singh, Brian Rivers, James W. Lillard, Rajesh Singh","doi":"10.1158/1538-7445.am2025-4972","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-4972","url":null,"abstract":"Liver cancer (LC) is one of the most devastating malignancies. Low socioeconomic status (SES), especially poverty, negatively affects HCC outcomes. Poverty is a risk factor in cancer incidence, late-stage diagnosis, and mortality for all racial/ethnic groups. This study aims to evaluate the correlation between LC incidence and Social Determinants of Health (SDOH), focusing on major ethnic groups (African American (AA) and European Americans (EA)) in Georgia (GA). We utilized Geospatial Technology (GT) to analyze the connection between SDOH and LC prevalence in AA and EA populations in GA. This study incorporated county-level LC prevalence and association with SES and health disparities. The robust data mining (All of Us, NCI Cancer Atlas, and SEER) enabled us to explore the association between SDOH and LC in the spatial context. Integrating spatial and non-spatial data on LC prevalence to SES will help predict and formulate LC prevention methods. The GT's secondary data analysis revealed that LC affects minority communities in GA. The GT analysis further demonstrates poverty, uninsured rates, and food insecurity were positively correlated with higher LC incidence, reflecting the impact of economic instability on health outcomes. Limited access to exercise and higher crime rates in some counties further compounded risks, likely through indirect effects on stress and health behaviors. Racial disparities were prominent, with AA populations experiencing a disproportionately higher burden of LC compared to EA. The analysis highlighted that GA counties with elevated poverty rates (20-33%) and higher uninsured percentages (18-26%) exhibited increased LC incidence, particularly within AA populations. In these communities, the LC rates reached 20-24 cases per 100, 000 for AA males and 15-20 for AA females, which is significantly higher compared to the rates for EA males at 10-16 cases and EA females at 6-12 cases. The study underscored notable racial disparities, revealing that AA populations bear a disproportionate burden of LC, linked to a complex interplay of socioeconomic, behavioral, and systemic influences. Additionally, the findings indicated that AA individuals had lower levels of educational attainment, with 10-20% holding a bachelor's degree, alongside higher rates of smoking (20-30%) and alcohol use (15-25%). Conversely, EA populations demonstrated more favorable SES indicators, including lower unemployment rates (6-12%) and a greater percentage with higher education (20-25%). These findings underscore the intricate interplay of socioeconomic, behavioral, and systemic factors driving LC disparities. Our finding demonstrates that SES is an essential factor that modulates LC incidences in underserved minority populations in GA. Hence, understanding the association between socioeconomic disparities will help predict and prevent LC more effectively. Citation Format: Amit Kumar Srivastav, Manoj Kumar Mishra, Shailesh Singh, Brian Rivers, James W. Li","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"66 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 5524: Developing KRASG12C inhibitor-resistant tumor models for efficacy evaluation of next-generation anticancer therapies","authors":"Jian Feng, Dan Zhang, Aaron Hua, Chenpan Nie, Jessie(Jingjing) Wang, Ludovic Bourre, Jun Zhou, Peng Wang","doi":"10.1158/1538-7445.am2025-5524","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-5524","url":null,"abstract":"Background: For decades, KRAS was considered undruggable due to the lack of suitable binding sites. However, advancements in bioengineering and chemistry have enabled the approval of targeted therapies. Success was first seen with allele-specific targeting of KRASG12C in non-small cell lung cancer (NSCLC), leading to the approval of sotorasib (AMG510, LumakrasTM). Despite its clinical benefits, resistance emerged in some patients due to secondary KRAS mutations, which necessitates next-generation or combination therapy development. In this study, we outline the development of KRASG12C inhibitor-resistant models overcome this hurdle. Methods: Secondary KRAS mutations (Y96D/C/S, H95D/Q/R, R68S, Q61H, A59T/S, and Q99L) were introduced by CRISPR/Cas9 in MIA PaCa-2 with a homozygous KRASG12C mutation. Knock-in of point mutation was validated by Sanger sequencing. Cell viability was assessed by CellTiter-Glo (CTG) with AMG510 and MRTX849 (Adagrasib, KrazatiTM). RAS-MAPK pathway activity was evaluated by western blot. Xenograft models of MIA PaCa-2 cells with Y96D/C, H95D/Q/R, R68S, Q61H and A59T were established. Additionally, in vitro chronic dosing of AMG510 generated AMG510-resistant MIA PaCa-2 and NCI-H358 cell lines were validated by CellTiter-Glo and western blot. RNA-seq identified potential resistance mechanisms. Xenograft models were also established. Results: A successful homozygous point mutation knock-in was confirmed by Sanger sequencing. Cells expressing double-mutant alleles KRAS G12C Y96D/C/S, A59T/S and R68S showed resistance to both AMG510 and MRTX849, while KRAS G12C H95D/Q/R was more resistant to MRTX849, and KRAS G12C Q61H, Q99L didn’t show significant resistance. Persistent phosphorylated ERK (pERK) and pRSK levels indicated sustained RAS-MAPK activity in cells expressing KRAS G12C Y96D, H95D, A59T/S, and R68S, even at high KRAS inhibitor concentrations. Furthermore, a KRAS G12C Y96D/C, A59T, Q61H, R68S and H95D/Q/R double mutant cell-derived xenograft was established in vivo. Additionally, MIA PaCa-2 AMG510-resistant and NCI-H358 AMG510-resistant cells showed resistance to AMG510 and MRTX849 in cell viability assays. RNA-seq data identified c-MET amplification in AMG510-resistant MIA PaCa-2 cell, while FGFR1/3/4 amplification was found in AMG510-resistant NCI-H358 cells. Conclusion: CRISPR/Cas9-engineered KRAS secondary mutations cell lines displayed differentially resistant profile to KRASG12C inhibitors, and drug-induced resistant cell models developed in vitro displayed KRAS-independent mechanisms of resistance. These novel cell models offer a valuable preclinical platform to evaluate therapeutic strategies to overcome resistance to KRAS-targeted therapies. Citation Format: Jian Feng, Dan Zhang, Aaron Hua, Chenpan Nie, Jessie(Jingjing) Wang, Ludovic Bourre, Jun Zhou, Peng Wang. Developing KRASG12C inhibitor-resistant tumor models for efficacy evaluation of next-generation anticancer therapies [abstract]. In: Proceedings of the","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"24 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 61: Establishment of translational luciferase-based cancer models to evaluate antitumoral therapies","authors":"Martin R. Ramos-Gonzalez, Nagabhishek S. Natesh, Satyanarayana Rachagani, James Amos-Landgraft, Haval Shirwan, Esma S. Yolcu, Jorge G. Gomez-Gutierrez","doi":"10.1158/1538-7445.am2025-61","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-61","url":null,"abstract":"There is an increased need for translational cancer models in research that can serve as more clinically relevant platforms to better study how cancer develops, the formation of metastases, and for the evaluation of the efficacy of new antitumoral therapies. Orthotopic cancer models represent a valuable opportunity to better understand how cancer cells behave and produce tumors in their primary organs, as well as how the local microenvironment can affect the tumor development. However, studying a growing tumor inside of an animal’s body carries several challenges, like the difficulty to accurately detect the tumor’s presence or changes in size since its location is not always easily accessible. To address this situation, we developed luciferase-based cancer cell lines that can produce bioluminescence (BL) and when inoculated orthotopically, they produce solid tumors that can be detected in live animals, allowing for a more accurate model to evaluate antitumoral therapies. We stably transfected the triple negative breast cancer (TNBC) cell line from human origin HCC1937, and the murine cell line 4T1, as well as the murine lung cancer cell line TC-1 with a luciferase expressing plasmid. After transfection, the luciferase activity was tested in vitro and once confirmed these luciferase-expressing cell lines were inoculated orthotopically into synergic animals. We successfully established orthotopic BL tumors that could be detected by bioluminescence imaging (BLI), as well as the detection of distal metastases by this method. The signal from the tumors in vivo correlated with the signal detected from the ex vivo organs, confirming the high accuracy and sensitivity of the use of BL as a detection method for cancer models. Interestingly, we confirmed a change in phenotype after the plasmid internalization in the cell line HCC1937/luc2. This cell line modified its response to an oncolytic adenovirus virotherapy, downregulating its antiviral response and becoming more sensitive to be infected and killed by these viruses. This highlights the importance of confirming the desired phenotype of a cell line remains unaltered after a genetic modification, as in our case, a plasmid insertion. In our study, we offer clinically relevant bioluminescent orthotopic cancer models that can be used to accurately evaluate the efficacy of antitumoral therapies by the quantification of BL signal coming from live animals. This method facilitates the monitoring of the tumoral growth and the appearance of metastases, with the advantage of allowing for multiple readings over time on live animals to assess the efficacy of antitumoral therapies. Citation Format: Martin R. Ramos-Gonzalez, Nagabhishek S. Natesh, Satyanarayana Rachagani, James Amos-Landgraft, Haval Shirwan, Esma S. Yolcu, Jorge G. Gomez-Gutierrez. Establishment of translational luciferase-based cancer models to evaluate antitumoral therapies [abstract]. In: Proceedings of the American Association for Cancer Researc","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"7 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 824: Comparative pharmacokinetics (PK) of targeted tissue factor tTF-NGR when intravenously applied alone or in combination with preceding trabectedin","authors":"Christian Schwöppe, Caroline Brand, Kathrin Hessling, Heike Hintelmann, Andrew F. Berdel, Georg Lenz, Torsten Kessler, Manfred Fobker, Christoph Schliemann, Wolfgang E. Berdel","doi":"10.1158/1538-7445.am2025-824","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-824","url":null,"abstract":"Trabectedin is a treatment option for relapsed/refractory soft tissue sarcomas (STS). CD13 is a neutral aminopeptidase expressed on invasive endothelial cells (EC) such as in the tumor vasculature. CD13-targeted tissue factor (tTF-NGR) is a recombinant pro-coagulatory fusion protein with a molecular weight of 30381.98 g/mol which accumulates in the tumor vasculature leading to tumor vascular occlusion and tumor infarction. Giving both compounds in sequence could trap trabectedin inside tumors and increase its efficacy. Vice versa trabectedin optimizes activity of tTF-NGR by externalizing phosphatidylserine (PS) on the surface of EC. PK of safety patients treated at our hospital within a multicenter trial of a combination of trabectedin and tTF-NGR in advanced STS patients refractory to 1st line systemic therapy (TRABTRAP, EudraCT 2020-005858-21) were compared with PK from our phase I monotherapy study with tTF-NGR (EudraCT 2016-003042-85). We compared standard PK parameters for tTF-NGR at identical dose levels (1.0 to 3.0 mg/m2) from TRABTRAP and phase I within the same laboratory with identical methods and calculations. Although some PK differences between phase I and TRABTRAP were more pronounced at lower dose levels, global values such as Cmax, AUC, t1/2alpha, t1/2term, and Kel indicated an increased AUC with a delayed elimination of tTF-NGR when given after trabectedin. As tTF-NGR was always given daily, we measured the remaining tTF-NGR concentrations before subsequent applications and found significantly increased values in the combination protocol (1 mg/m2: p<0.0001; 3 mg/m2: p<0.0002) when compared with the phase I values, suggesting a possible accumulation of tTF-NGR which we did not observe with monotherapy. A specific way of tTF-NGR elimination in the vascular system is the internalization of the tTF-NGR:CD13 complex into EC. Using flow cytometry and fluorescence labeling with tTF-NGR and EC in vitro, expression of CD13 on EC was slightly diminished by trabectedin exposure. Also, tTF-NGR binding to CD13 (p<0.01) and internalization (p=0.01) decreased when tested on control and trabectedin-exposed EC. Both lead to more tTF-NGR molecules remaining in the circulation, explaining part of the delayed elimination. Further, we compared functionality of tTF-NGR in the plasma of patients from phase I and TRABTRAP. On the basis of equal protein amounts and without influence of confounders such as storage, the ability of factor VIIa:tTF-NGR:CD13 to activate factor X to Xa was higher when trabectedin was given to the patients before. Among possible explanations are the decreased liver protease levels after trabectedin, which could influence the functionality of tTF-NGR. In summary, these results explain why the Maximum Tolerated Dose level for tTF-NGR established in the TRABTRAP safety cohort is lower than the 3 mg/m2 in the phase I study. Citation Format: Christian Schwöppe, Caroline Brand, Kathrin Hessling, Heike Hintelmann,","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"4 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 1197: Association of increasing alcohol intake over the lifetime with colorectal adenoma and colorectal cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial","authors":"Caitlin P. O'Connell, Sonja I. Berndt, Kenechukwu Chudy-Onwugaje, Andrew T. Kunzmann, Wen-Yi Huang, Kathryn Hughes Barry, Erikka Loftfield","doi":"10.1158/1538-7445.am2025-1197","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-1197","url":null,"abstract":"Introduction: Recent alcohol drinking has been associated with higher colorectal cancer (CRC) risk. However, research on lifetime alcohol drinking in relation to colorectal adenoma (CRC precursor) and CRC risk is limited. We aimed to estimate the association of average lifetime alcohol drinking and change in alcohol consumption over adulthood with incident colorectal adenoma and cancer. Methods: U.S. adults enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were asked about alcohol intake during four age periods (18-24, 25-39, 40-54, and ≥55 years) as part of a dietary history questionnaire (DHQ). Participants were also asked about alcohol consumption in the year prior to the DHQ (reflecting current drinking). Average lifetime alcohol intake was calculated as average drinks per week from early adulthood (age 18-24) until age at DHQ completion (median of 65 years). Change in alcohol intake was defined as the difference between alcohol intake at the DHQ and age 18-24. Incident adenomas (n=807, including 196 advanced adenomas) were defined in the screening arm based on a negative baseline trial screen and a positive follow-up trial screen 3 or 5 years later; controls (n=11, 446) were defined based on negative baseline and follow-up screens. CRC incidence (n=1, 679) was defined based on 20 years of cancer follow-up in both trial arms. Multivariable-adjusted logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for incident adenoma. Multivariable-adjusted Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% CI for CRC. Models adjusted for a number of potential confounders including demographic factors, body mass index, family history of CRC, and various dietary factors. P-values for interaction between alcohol intake and sex were computed using likelihood ratio tests comparing models with and without the interaction terms. Results: Increasing alcohol intake by 1 drink/day every 10 years was associated with higher risk of adenoma (OR=1.19, CI: 1.02-1.39), advanced adenoma (OR=1.41, CI: 1.11-1.79), and CRC (HR=1.11, CI: 0.99-1.24). Among men, drinking ≥14 drinks/week, compared to <1 drink/week, throughout adulthood was positively associated with risk of advanced adenoma (OR=1.83, CI: 0.95-3.50) as well as rectal (HR=1.80, CI: 1.03-3.13) and distal colon (HR=1.54, CI: 0.98-2.42) but not proximal colon (HR=0.96, CI: 0.71-1.31) cancer. Associations tended to be less pronounced among women, but with limited case numbers, we found no evidence of significant effect modification by sex (p-interaction>0.05). Conclusions: Our study suggests that increasing alcohol intake over the lifetime and higher average lifetime alcohol drinking is associated with a higher risk of advanced colorectal adenoma and CRC. Citation Format: Caitlin P. O'Connell, Sonja I. Berndt, Kenechukwu Chudy-Onwugaje, Andrew T. Kunzmann, Wen-Yi Huang, Kathryn Hughes Barr","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"17 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}