Combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (OPTIMIZE-1): a single-arm, multicentre phase 1b/2 study

The Lancet Oncology, Год журнала: 2024, Номер 25(7), С. 853 - 864

Опубликована: Июнь 1, 2024

Язык: Английский

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Differences in tumor-associated T-cell receptor repertoires between early-onset and average-onset colorectal cancer

JNCI Journal of the National Cancer Institute, Год журнала: 2024, Номер 116(10), С. 1645 - 1653

Опубликована: Июнь 19, 2024

The incidence of colorectal cancer (CRC) among individuals younger than age 50 (early-onset CRC [EOCRC]) has substantially increased, and yet the etiology molecular mechanisms underlying this alarming rise remain unclear. We compared tumor-associated T-cell repertoires between EOCRC average-onset (AOCRC) to uncover potentially unique immune microenvironment-related features by onset. Our discovery cohort included 242 patients who underwent surgical resection at Cleveland Clinic from 2000 2020. was defined as years diagnosis (N = 126) AOCRC 60 or older 116). receptor (TCR) abundance clonality were measured immunosequencing tumors. Logistic regression models used evaluate associations TCR repertoire onset, adjusting for sex, race, tumor location, stage. Findings replicated in 152 1984 cases Molecular Epidemiology Colorectal Cancer Study. tumors had significantly higher diversity with (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.32 0.61, P < .0001). This association also observed replication (OR 0.74, CI 0.62 0.89, .0013). No significant differences either cohort. Higher diversity, suggesting a more diverse intratumoral response, is frequently AOCRC. Further studies are warranted investigate role adaptive response broadly outcomes EOCRC.

Язык: Английский

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Pancreatic cancer: failures and hopes—a review of new promising treatment approaches

Exploration of Targeted Anti-tumor Therapy, Год журнала: 2025, Номер 6

Опубликована: Март 18, 2025

Pancreatic cancer is a challenging disease with limited treatment options and high mortality rate. Just few therapy advances have been made in recent years. Tumor microenvironment, immunosuppressive features mutational status represent important obstacles the improvement of survival outcomes. Up to now, first-line did achieve median overall less than 12 months this discouraging data lead clinicians all over world focus their efforts on various fields investigation: 1) sequential cycling different systemic order overcome mechanisms resistance; 2) discovery new predictive bio-markers, target specific patient population; 3) combination treatment, modulate tumor microenvironment pancreatic cancer; 4) modalities delivery drugs pass physical barrier desmoplasia stroma. This review shows future directions strategies advanced through deep analysis these macro areas research.

Язык: Английский

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Advances in Drug Therapy for Metastatic Pancreatic Ductal Adenocarcinoma

Journal of Cancer, Год журнала: 2024, Номер 15(8), С. 2214 - 2228

Опубликована: Янв. 1, 2024

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a notably poor prognosis.A large number of patients PDAC develop metastases before they are diagnosed metastatic pancreatic cancer (mPDAC).For mPDAC, FOLFIRINOX or gemcitabine plus nab-paclitaxel the current first-line treatments.It important to note, however, that many will fail chemotherapy because drug resistance.Heterogeneous tumors and complex tumor microenvironments key factors.As result, clinical researchers exploring variety alternative treatment modalities.Current understanding molecular signature immune landscape has motivated emergence different targeted immune-based therapeutic approaches, some which have shown promising results.The purpose this review discuss new targets drugs for mPDAC in terms specific pathogenic factors such as metabolic vulnerability, DNA damage repair system, microenvironment order identify potential vulnerabilities hopefully improve prognosis patients.

Язык: Английский

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Combination of farnesyl-transferase inhibition with KRAS G12D targeting breaks down therapeutic resistance in pancreatic cancer

Pathology & Oncology Research, Год журнала: 2024, Номер 30

Опубликована: Дек. 2, 2024

Pancreatic adenocarcinoma is one of the deadliest forms cancer with no effective therapeutic options. A KRAS mutation can be found in up to 90% all pancreatic tumors, making it a promising target. The introduction new inhibitors has been milestone history mutant tumors; however, resistance limits their efficacy. Thus, options, including combination therapies, are urgently needed. Recently, we have shown that G12C farnesyl-transferase exert synergistic antitumor effects. Here, provide evidence for feasibility this combinational approach break down G12D cancer. Although 3D environment dramatically sensitizes cells MRTX1133 treatment, effect drug present both 2D and PANC1 model, which showed high 2D. effects treatment show an association inhibition farnesylated regulatory proteins, HRAS RHEB, along expression level KRAS. Our study warrants further investigation potential applicability adenocarcinoma.

Язык: Английский

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Bis-pyrazole as receptor interacting protein 1 kinase inhibitor: Synthesis, preliminary biological evaluation against pancreatic cancer cell line and its docking studies

Results in Chemistry, Год журнала: 2024, Номер 7, С. 101447 - 101447

Опубликована: Янв. 1, 2024

The pyrazole heterocycle displayed versatile pharmacological activity ranging from anti-inflammatory to antiviral. Herein, we report the synthesis of bis-pyrazole as receptor- interacting protein 1 kinase inhibitor and evaluated for antiproliferative against pancreatic cancer line, PANC-1. Among twelve compounds, three candidates cytotoxicity IC50 value in single digit micromolar concentration. From preliminary evaluation, compound 31 emerged a potential with an = 4.1 µM. lead showed similar comparison positive control, doxorubicin. docking studies confirm that these analogs may require further investigation improve potency.

Язык: Английский

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Safety, Efficacy, and Biomarker Results of a Phase 1b/2 Study Combining the CD40 Agonist Mitazalimab with mFOLFIRINOX in Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC); Results of the OPTIMIZE-1 Trial

Опубликована: Янв. 1, 2024

Язык: Английский

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