Fernand Bteich

Background/Objectives: PI3K/AKT/mTOR is a key pathway in cell proliferation, metabolism, and survival. Activating PIK3CA mutations are seen in up to 20% of colorectal cancers and are associated with increased cyclo-oxygenase-2 (COX-2) expression. Recent studies demonstrated a significant survival benefit from taking low-dose aspirin, a nonselective COX inhibitor, supporting further exploration of the synergistic effects of combined PI3Kα inhibitor (inavolisib) and COX-2 inhibitor (celecoxib) therapy. Methods: The effects of celecoxib–inavolisib combination treatment were tested on human colorectal cancer cell lines and patient-derived organoid models. Experiments included cell viability and colony formation assays, immunoblotting, and immunofluorescence. Results: We found that celecoxib and inavolisib demonstrated synergy in suppressing the growth of colorectal cancer cell lines, grown in both 2D and 3D cell culture, regardless of PIK3CA mutation status. In patient-derived organoid models, while synergy was seen in both organoids, growth of the PIK3CA mutated organoid was more potently suppressed. Immunoblotting of cells after combination treatment showed decreased expression of mitogenic signaling marker p-AKT across all 2D cell lines and in both cell lines grown as 3D spheroids, as well as increased expression of apoptotic marker cPARP in four out of five 2D cell lines and in both cell lines grown as 3D spheroids. Immunofluorescence staining of organoids after combination treatment, however, showed no significant increase in expression of apoptotic marker Cas-3 nor in mitogenic marker Ki-67 in either organoid. Furthermore, an apoptosis assay performed on two cell lines showed no significant increase in Annexin V or phosphatidylserine staining. Conclusions: Celecoxib and inavolisib demonstrated synergy in suppressing the growth of both colorectal cancer cell lines and patient-derived organoids, though PIK3CA mutation status did not appear to affect drug efficacy in cell lines as it did in patient-derived organoids. Potential compensatory or resistance mechanisms might include oncogene drivers in the MAPK/ERK pathway. When compared to monotherapy, combination therapy was the only drug condition to significantly increase the percentage of apoptotic cells based on Annexin V and phosphatidylserine staining, and this effect was only seen in the PIK3CA mutated cell line. Ultimately, our findings provide preliminary support for celecoxib–inavolisib combination treatment as a rational therapeutic avenue warranting further preclinical investigation.

Gastrointestinal (GI) cancers represent a significant global health burden, with high morbidity and mortality often linked to late-stage detection and metastatic disease. The progression of these malignancies is critically driven by angiogenesis, the formation of new blood vessels, and the surrounding dynamic tumor microenvironment (TME), a complex ecosystem comprising various cell types and non-cellular components. This comprehensive review, based on a systematic search of the PubMed database, synthesizes the existing literature to define the intertwined roles of angiogenesis and the TME in GI tumorigenesis. The TME’s influence creates conditions favorable for tumor growth, invasion, and metastasis, but sometimes induces resistance to current therapies. Available therapeutic strategies for inhibiting angiogenesis involve antibodies and oral tyrosine kinase inhibitors, while immune modulation within the tumor microenvironment is mainly achieved through checkpoint inhibitor antibodies and chemotherapy. Creative emerging strategies encompassing cellular therapies, bispecific antibodies, and new targets such as CD40, DLL4, and Ang2, amongst others, are focused on inhibiting proangiogenic pathways more profoundly, reversing resistance to prior drugs, and modulating the TME to enhance therapeutic efficacy. A deeper understanding of the complex interactions between components of the TME is crucial for addressing the unmet need for novel and effective therapeutic interventions against aggressive GI cancers.

Claudins, a family of tetraspan transmembrane proteins, are critical to the integrity of tight junctions in epithelia and endothelia, influencing cellular processes such as development, differentiation, and apoptosis. Abnormal claudin expression is associated with various malignancies, particularly affecting tissue architecture and potentially facilitating tumor invasion and metastasis. In this comprehensive review, we explore the multifaceted functions of claudins: their expression, specific roles in cancer with a focus on hepato-pancreato-biliary malignancies and highlight their potential as therapeutic targets. We discuss current claudin-targeted therapies, including monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engager and chimeric antigen receptor T-cell therapies. These approaches show promise in pre-clinical and clinical studies, particularly in hepato-pancreato-biliary cancers with large unmet needs. Despite these early signs of efficacy, challenges remain in effectively targeting these proteins due to their structural resemblance and overlapping functions.

Human epidermal growth factor 2 (HER2) is a tyrosine kinase receptor that interacts with multiple signaling pathways related to cellular growth and proliferation. Overexpression or amplification of HER2 is linked to various malignancies, and there have been decades of research dedicated to targeting HER2. Despite the landmark ToGA trial, progress in HER2-positive gastrointestinal malignancies has been hampered by drug resistance. This review examines current HER2 expression patterns and therapies for gastroesophageal, colorectal, biliary tract, and small bowel cancers, while dissecting potential resistance mechanisms that limit treatment effectiveness.

Colorectal cancer (CRC) is a heterogeneous disease with a myriad of alterations at the cellular and molecular levels. Kristen rat sarcoma (KRAS) mutations occur in up to 40% of CRCs and serve as both a prognostic and predictive biomarker. Oncogenic mutations in the KRAS protein affect cellular proliferation and survival, leading to tumorigenesis through RAS/MAPK pathways. Until recently, only indirect targeting of the pathway had been investigated. There are now several KRAS allele-specific inhibitors in late-phase clinical trials, and many newer agents and targeting strategies undergoing preclinical and early-phase clinical testing. The adequate treatment of KRAS-mutated CRC will inevitably involve combination therapies due to the existence of robust adaptive resistance mechanisms in these tumors. In this article, we review the most recent understanding and findings related to targeting KRAS mutations in CRC, mechanisms of resistance to KRAS inhibitors, as well as evolving treatment strategies for KRAS-mutated CRC patients.

E16157 Background: BTCs are the second most common primary hepatobiliary malignancy with rising incidence and mortality worldwide. Individual characterization of BTCs at a genomic level is critical to tailor management strategies. Currently available data stem from studies in predominantly White populations. We conducted a retrospective study to determine the demographic, clinical and survival profiles of patients with BTCs seen in our center, who had been tested for genomic alterations. Methods: We identified 69 patients with BTCs diagnosed between 2015-2022 who had tissue-based genomic results available. Chi-square test was used to compare frequency distributions. Univariate analysis with cox regression model and multivariate cox proportional hazards test were conducted. Kaplan-Meier curves were used to assess overall survival (OS). Results: Median age at diagnosis was 67 years and median follow-up time was 15.5 months. Racial and ethnic minority populations were highly represented with 41% Hispanic, 29% Black and 17% White patients. ECOG performance status (PS) ranged between 0-2 at diagnosis. Most patients (40%) had stage IV BTC, with intrahepatic cholangiocarcinoma (CCA) being most prevalent (48%). On univariate modeling, variables associated with a shorter OS were age (HR 1.03, 95% CI 1.00-1.07, p = 0.05) and ECOG PS of 2 (HR 7.03, 95% CI 1.49-33.3, p = 0.014). In a multivariate model, ECOG PS 2 was independently associated with a shorter OS. The most common mutations (N, %) found on NGS were TP53 (28, 41%), KRAS (13, 19%), ARID1A (11, 16%), PIK3CA (9, 13%), ERBB2 (5, 7%) and FGFR2 (5, 7%). Median tumor mutation burden (TMB) was 4 Mut/Mb, with 18.9% having hypermutated (≥10 Mut/Mb) BTCs. Potentially actionable targets were found in 40 (58%) patients, 5.8% of which received targeted therapies with a median OS of 27 months (median OS of entire cohort was 22.8 months). KRAS mutation was significantly less common in intrahepatic CCA compared to the other BTC subtypes (p = 0.016). Race or ethnicity were not found to have a significant association with mutation frequency (Table). TP53 and ARID1A mutations were associated with a trend towards reduced OS in univariable analysis, with HR = 1.46 (p = 0.29) and HR = 1.64 (p = 0.28) respectively. Conclusions: Extensive genomic diversity was observed among BTC patients in our center which serves a large minority population. Studies with larger sample size are required to expand our understanding of the genomic spectrum in BTCs, its therapeutic and survival implications.

Over the last few decades, changes in diagnostic and treatment paradigms have greatly advanced cancer care and improved outcomes