Pancreatic cancer: Advances and challenges

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1729 - 1754

Published: April 1, 2023

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. tumors are characterized by a complex microenvironment that orchestrates metabolic alterations supports milieu interactions among various cell types within this niche. In review, we highlight foundational studies driven our understanding these processes. We further discuss recent technological advances continue to expand complexity. posit clinical translation research endeavors will enhance currently dismal survival rate recalcitrant disease.

Language: Английский

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Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Dec. 18, 2023

Metastatic dissemination of solid tumors, a leading cause cancer-related mortality, underscores the urgent need for enhanced insights into molecular and cellular mechanisms underlying metastasis, chemoresistance, mechanistic backgrounds individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is mitogen-activated protein kinase (MAPK) pathway, encompassing RAS-RAF-MAPK (MEK)-extracellular signal-related (ERK) pathway. RAF primary mediator MAPK responsible sequential activation downstream targets, such as MEK transcription factor ERK, which control numerous physiological processes, including organism development, cell cycle control, proliferation differentiation, survival, death. Defects in this associated with diseases cancer. (RAFi) combined blockers represent an FDA-approved therapeutic strategy RAF-mutant cancers, melanoma, non-small lung carcinoma, thyroid However, development therapy resistance cancer cells remains important barrier. Autophagy, intracellular lysosome-dependent catabolic recycling process, plays critical role RAFi Thus, targeting autophagy could be novel treatment strategies cancers. In review, we delve deeper surrounding tumorigenesis RAFi-resistance. Furthermore, explore discuss ongoing next-generation profiles. Additionally, review sheds light on functional interplay between RAF-targeted therapies

Language: Английский

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Exploring treatment options in cancer: Tumor treatment strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: July 17, 2024

Traditional therapeutic approaches such as chemotherapy and radiation therapy have burdened cancer patients with onerous physical psychological challenges. Encouragingly, the landscape of tumor treatment has undergone a comprehensive remarkable transformation. Emerging fervently pursued modalities are small molecule targeted agents, antibody-drug conjugates (ADCs), cell-based therapies, gene therapy. These cutting-edge not only afford personalized precise targeting, but also provide enhanced comfort potential to impede disease progression. Nonetheless, it is acknowledged that these strategies still harbour untapped for further advancement. Gaining understanding merits limitations holds promise offering novel perspectives clinical practice foundational research endeavours. In this review, we discussed different modalities, including drugs, peptide antibody cell therapy, It will detailed explanation each method, addressing their status development, challenges, solutions. The aim assist clinicians researchers in gaining deeper diverse options, enabling them carry out effective advance more efficiently.

Language: Английский

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Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

New England Journal of Medicine, Journal Year: 2023, Volume and Issue: 389(23), P. 2125 - 2139

Published: Oct. 22, 2023

G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy KRAS inhibitors has yielded only modest efficacy. Combining the inhibitor sotorasib panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, may be effective strategy.

Language: Английский

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Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation

New England Journal of Medicine, Journal Year: 2023, Volume and Issue: 389(8), P. 710 - 721

Published: Aug. 23, 2023

Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity.In phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 400 mg) in patients who had advanced or metastatic solid tumors harbor mutation. The primary objective an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, biomarkers response resistance were also assessed.A total 137 (60 with non-small-cell lung cancer [NSCLC], 55 colorectal cancer, 22 other tumors) received divarasib. No dose-limiting toxic effects treatment-related deaths reported. Treatment-related adverse events occurred 127 (93%); grade 3 15 (11%) 4 event patient (1%). resulted dose reduction 19 (14%) discontinuation treatment (3%). Among NSCLC, confirmed observed 53.4% (95% confidence interval [CI], 39.9 66.7), the median progression-free survival 13.1 months CI, 8.8 could not be estimated). 29.1% 17.6 42.9), 5.6 4.1 8.2). Responses tumors. Serial circulating tumor DNA showed declines variant allele frequency associated identified genomic alterations may confer divarasib.Treatment durable clinical responses across G12C-positive tumors, mostly low-grade events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).

Language: Английский

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Adagrasib in Advanced Solid Tumors Harboring a KRAS^G12C Mutation

Journal of Clinical Oncology, Journal Year: 2023, Volume and Issue: 41(25), P. 4097 - 4106

Published: April 26, 2023

PURPOSE Adagrasib, a KRAS G12C inhibitor, has demonstrated clinical activity in patients with -mutated non–small-cell lung cancer (NSCLC) and colorectal (CRC). mutations occur rarely other solid tumor types. We report evaluation of the safety adagrasib tumors harboring mutation. METHODS In this phase II cohort KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249 ; Ib cohort), we evaluated (600 mg orally twice daily) advanced (excluding NSCLC CRC). The primary end point was objective response rate. Secondary points included duration response, progression-free survival (PFS), overall survival, safety. RESULTS As October 1, 2022, 64 were enrolled 63 treated (median follow-up, 16.8 months). median number prior lines systemic therapy 2. Among 57 measurable disease at baseline, responses observed 20 (35.1%) (all partial responses), including 7/21 (33.3%) pancreatic 5/12 (41.7%) biliary tract cancers. 5.3 months (95% CI, 2.8 to 7.3) PFS 7.4 8.6). Treatment-related adverse events (TRAEs) any grade 96.8% 3-4 27.0%; there no 5 TRAEs. TRAEs did not lead treatment discontinuation patients. CONCLUSION Adagrasib demonstrates encouraging is well tolerated rare pretreated tumors.

Language: Английский

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Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer

Cancer Discovery, Journal Year: 2023, Volume and Issue: 14(1), P. 49 - 65

Published: Oct. 17, 2023

There is a continuing debate about the proportion of cancer patients that benefit from precision oncology, attributable in part to conflicting views as which molecular alterations are clinically actionable. To quantify expansion clinical actionability since 2017, we annotated 47,271 solid tumors sequenced with MSK-IMPACT assay using two temporally distinct versions OncoKB knowledge base deployed 5 years apart. Between 2017 and 2022, observed an increase 8.9% 31.6% fraction harboring standard care (level 1 or 2) predictive biomarker therapy response almost halving carrying nonactionable drivers (44.2% 22.8%). In limited no actionability, TP53 (43.2%), KRAS (19.2%), CDKN2A (12.2%) were most frequently altered genes. Although clear progress has been made expanding availability oncology-based treatment paradigms, our results suggest continued unmet need for innovative therapeutic strategies, particularly cancers currently undruggable oncogenic drivers. See related commentary by Horak Fröhling, p. 18. This article featured Selected Articles Issue, 5.

Language: Английский

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Adagrasib: First Approval

Drugs, Journal Year: 2023, Volume and Issue: 83(3), P. 275 - 285

Published: Feb. 1, 2023

Language: Английский

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Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers

Cancer Discovery, Journal Year: 2024, Volume and Issue: 14(6), P. 994 - 1017

Published: April 9, 2024

Abstract RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor the active, GTP-bound state both mutant and wild-type variants canonical RAS isoforms with broad therapeutic potential for aforementioned unmet medical need. exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 KRAS. Notably, oral administration was tolerated in vivo drove profound tumor regressions multiple types mouse clinical trial KRASG12X xenograft models. Translational PK/efficacy PK/PD modeling predicted that daily doses 100 mg 300 would achieve control objective responses, respectively, patients tumors. Consistent this, we describe here responses two (at daily) advanced lung pancreatic adenocarcinoma, demonstrating initial an ongoing phase I/Ib (NCT05379985). Significance: The discovery enables first-ever evaluation targeted concurrent inhibition RAS-GTP We demonstrate broad-spectrum tolerable exposures induce preclinical models of, with, such This article featured Selected Articles from Issue, p. 897

Language: Английский

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Targeting KRAS in cancer

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(4), P. 969 - 983

Published: April 1, 2024

Language: Английский

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