Pancreatic Cancer: A Review of Current Treatment and Novel Therapies

Journal of Investigative Surgery, Journal Year: 2022, Volume and Issue: 36(1)

Published: Oct. 3, 2022

Pancreatic cancer is one of the leading causes for cancer-related deaths in United States. Majority patients present with unresectable or metastatic disease. For those that localized disease, a multidisciplinary approach necessary to maximize survival and optimize outcomes. The quality safety surgery pancreatic have improved recent years increasing adoption minimally invasive techniques surgical adjuncts. Systemic chemotherapy has also evolved impact survival. It now increasingly being utilized neoadjuvant setting, often concomitant radiation. Increased utilization genomic testing led better understanding their biology, thereby allowing clinicians consider potential targeted therapies. Similarly, agents such as PARP inhibitors immune checkpoint- emerged promising results. In summary, remains disease poor long-term However, developments outcomes changed practice past decade. This review summarizes current practices treatment milestones brought us where we are today, along emerging

Language: Английский

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New clinical trial design in precision medicine: discovery, development and direction

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

Published: March 4, 2024

Abstract In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to underestimation significant heterogeneity across participants in traditional “one-size-fits-all” trials, patient-centered trials could provide optimal therapy customization specific biomarkers were developed including basket, umbrella, platform trial designs under master protocol framework. recent years, successive FDA approval indications based on biomarker-guided demonstrated these new clinical ushering tremendous opportunities. Despite rapid increase number current research understanding designs, as compared remains limited. The majority focuses methodologies, there is lack in-depth insight concerning underlying biological logic designs. Therefore, we this comprehensive review discovery development their perspective medicine. Meanwhile, discuss future directions potential design view “Precision Pro”, “Dynamic Precision”, “Intelligent Precision”. This would assist trial-related researchers enhance innovation feasibility by expounding logic, which be essential accelerate progression

Language: Английский

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Homologous Recombination Deficiencies and Hereditary Tumors

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 23(1), P. 348 - 348

Published: Dec. 29, 2021

Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, RAD51C, and RAD51D, lead to inherited susceptibility specific types of cancers, including those breast, ovaries, prostate, pancreas. The penetrance germline pathogenic each gene varies, whereas all their associated protein products are indispensable maintaining high-fidelity repair system by HR. present review summarizes basic molecular mechanisms components that collectively play role genomic integrity against damage clinical implications on type hereditary tumor.

Language: Английский

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Characterization of the genomic landscape in large-scale Chinese patients with pancreatic cancer

EBioMedicine, Journal Year: 2022, Volume and Issue: 77, P. 103897 - 103897

Published: Feb. 26, 2022

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with an extremely poor prognosis. Effective targets for anticancer therapy confirmed in PDAC are limited. However, the characteristics of genomics have not been fully elucidated large-scale patients from China.We collected both blood and tissue samples 1080 Chinese pancreatic cancer retrospectively investigated genomic landscape using next-generation sequencing (NGS).We found recurrent somatic mutations KRAS (83.2%), TP53 (70.6%), CDKN2A (28.8%), SMAD4 (23.0%), ARID1A (12.8%) CDKN2B (8.9%) patients. Compared primary cancers, more alterations accumulated especially cell cycle regulatory gene variants (45.4% vs 31.6%, P < 0.001) were observed metastatic tumors. The most common mutation site p.G12D (43.6%) cancer. Patients significantly associated older age other three driver genes, while wild-type contained fusion alternative mechanisms RTK/Ras/MAPK pathway including number clinically targetable mutations. cohort lower than those Western cohorts (all 0.05). A total 252 (23.3%) core DNA damage response (DDR) detected. ATM (n =59, 5.5%) was frequent mutant DDR China. germline younger (P = 0.018), likely to accumulate lesions had higher TMB levels 0.001). In addition, genes carrying mutually exclusive 0.001).We demonstrated real-world China which may promising implications further clinical significance drug development.The funders listed Acknowledgement.

Language: Английский

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POLQ inhibition elicits an immune response in homologous recombination–deficient pancreatic adenocarcinoma via cGAS/STING signaling

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(11)

Published: March 28, 2023

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that harbors mutations in homologous recombination-repair (HR-repair) proteins 20%-25% of cases. Defects HR impart specific vulnerability to poly ADP ribose polymerase inhibitors and platinum-containing chemotherapy tumor cells. However, not all patients who receive these therapies respond, many initially respond ultimately develop resistance. Inactivation the pathway associated with overexpression theta (Polθ, or POLQ). This key enzyme regulates microhomology-mediated end-joining (MMEJ) double-strand break (DSB) repair. Using human murine HR-deficient PDAC models, we found POLQ knockdown synthetically combination genes such as BRCA1 BRCA2 DNA damage repair gene ATM. Further, enhances cytosolic micronuclei formation activates signaling cyclic GMP-AMP synthase-stimulator interferon (cGAS-STING), leading enhanced infiltration activated CD8+ T cells BRCA2-deficient tumors vivo. Overall, POLQ, mediator MMEJ pathway, critical for DSB PDAC. Its inhibition represents synthetic approach blocking growth while concurrently activating cGAS-STING enhance immune infiltration, highlighting what believe be new role environment.

Language: Английский

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Clinical and biomarker analyses of sintilimab plus gemcitabine and cisplatin as first-line treatment for patients with advanced biliary tract cancer

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 11, 2023

Abstract The prognosis of biliary tract cancer (BTC) remains unsatisfactory. This single-arm, phase II clinical trial (ChiCTR2000036652) investigated the efficacy, safety, and predictive biomarkers sintilimab plus gemcitabine cisplatin as first-line treatment for patients with advanced BTCs. primary endpoint was overall survival (OS). Secondary endpoints included toxicities, progression-free (PFS), objective response rate (ORR); multi-omics were assessed exploratory objective. Thirty enrolled received treatment, median OS PFS 15.9 months 5.1 months, ORR 36.7%. most common grade 3 or 4 treatment-related adverse events thrombocytopenia (33.3%), no reported deaths nor unexpected safety events. Predefined biomarker analysis indicated that homologous recombination repair pathway gene alterations loss-of-function mutations in chromatin remodeling genes presented better tumor outcomes. Furthermore, transcriptome revealed a markedly longer associated higher expression 3-gene effector T cell signature an 18-gene inflamed signature. Sintilimab meets pre-specified displays acceptable profile, multiomics potential are identified warrant further verification.

Language: Английский

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Consensus, debate, and prospective on pancreatic cancer treatments

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Oct. 10, 2024

Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite improvement multi-modality treatment strategies, prognosis pancreatic was not improved dramatically. For resectable or borderline patients, surgical strategy centered on improving R0 resection rate is consensus; however, role neoadjuvant therapy in patients and optimal chemotherapy with without radiotherapy were debated. Postoperative adjuvant gemcitabine/capecitabine mFOLFIRINOX recommended regardless margin status. Chemotherapy as first-line for advanced metastatic included FOLFIRINOX, gemcitabine/nab-paclitaxel, NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan only standard care second-line therapy. Immunotherapy an innovative although anti-PD-1 antibody currently agent approved by MSI-H, dMMR, TMB-high tumors, which represent very small subset cancers. Combination strategies to increase immunogenicity overcome immunosuppressive tumor microenvironment may sensitize immunotherapy. Targeted therapies represented PARP KRAS inhibitors are also under investigation, showing benefits progression-free survival objective response rate. This review discusses current modalities highlights cancer.

Language: Английский

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Deep Learning Artificial Intelligence Predicts Homologous Recombination Deficiency and Platinum Response From Histologic Slides

Journal of Clinical Oncology, Journal Year: 2024, Volume and Issue: 42(30), P. 3550 - 3560

Published: July 31, 2024

PURPOSE Cancers with homologous recombination deficiency (HRD) can benefit from platinum salts and poly(ADP-ribose) polymerase inhibitors. Standard diagnostic tests for detecting HRD require molecular profiling, which is not universally available. METHODS We trained DeepHRD, a deep learning platform predicting hematoxylin eosin (H&E)–stained histopathological slides, using primary breast (n = 1,008) ovarian 459) cancers The Cancer Genome Atlas (TCGA). DeepHRD was compared four standard 349) 141) multiple independent data sets, including platinum-treated clinical cohorts RECIST progression-free survival (PFS), complete response (CR), overall (OS) endpoints. RESULTS predicted held-out H&E-stained cancer slides in TCGA an AUC of 0.81 (95% CI, 0.77 to 0.85). This performance confirmed two (AUC, 0.76 [95% 0.71 0.82]). In external metastatic cohort, samples as had higher CR 0.54 0.93]) 3.7-fold increase median PFS (14.4 v 3.9 months; P .0019) hazard ratio (HR) 0.45 ( .0047). There were no significant differences nonplatinum treatment outcome by status three cohorts, 0.39) (HR, 0.98, .95) taxane-treated cancer. Through transfer high-grade serous cancer, DeepHRD-predicted better OS after first-line 0.46; .030) neoadjuvant 0.49; .015) therapy cohorts. CONCLUSION predict directly routine H&E across slide scanners, tissue fixation variables. When testing, classified 1.8- 3.1-fold more patients HRD, exhibited platinum-specific

Language: Английский

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Hereditary Pancreatic Cancer: Advances in Genetic Testing, Early Detection Strategies, and Personalized Management

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(2), P. 367 - 367

Published: Jan. 9, 2025

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with five-year survival rate of approximately 13% for advanced stages. While the majority PDAC cases are sporadic, significant subset attributable to hereditary and familial predispositions, accounting 25% cases. This article synthesizes recent advancements in understanding, detection, management pancreatic cancer (PC). Results: Our review highlights critical role genetic testing (GT) identifying high-risk individuals (HRIs), germline pathogenic variants (PVs) found up 20% Since implementation next-generation sequencing (NGS) panels 2014, detection capabilities have been significantly enhanced. HRIs can be included screening programs that facilitate early PDAC. Early strategies, including use microribonucleic acid (miRNAs) signatures novel imaging techniques like hyperpolarized 13C-magnetic resonance spectroscopy (MRS) shown promising results. The identification or mutations homologous recombination (HR) genes plays predictive response various treatments, prolonging patient survival. Discussion: Universal PDAC, as recommended by National Comprehensive Cancer Network (NCCN), now standard practice, facilitating at-risk enabling targeted surveillance intervention. Multidisciplinary management, integrating counseling, imaging, gastrointestinal services, essential optimizing outcomes. Conclusions: Advances biomarker research transforming landscape PC management. personalized treatment strategies pivotal improving rates. Ongoing multi-institutional efforts crucial validating biomarkers developing preventive measures, ultimately aiming reduce burden this aggressive cancer.

Language: Английский

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Double‐strand DNA break repair: molecular mechanisms and therapeutic targets

MedComm, Journal Year: 2023, Volume and Issue: 4(5)

Published: Oct. 1, 2023

Abstract Double‐strand break (DSB), a significant DNA damage brought on by ionizing radiation, acts as an initiating signal in tumor radiotherapy, causing cancer cells death. The two primary pathways for DSB repair mammalian are nonhomologous end joining (NHEJ) and homologous recombination (HR), which cooperate compete with one another to achieve effective repair. mechanism depends numerous regulatory variables. recognition the recruitment of components, instance, depend MRE11–RAD50–NBS1 (MRN) complex Ku70/80 heterodimer/DNA–PKcs (DNA–PK) complex, whose control is crucial determining pathway choice efficiency HR NHEJ. In‐depth elucidation pathway's molecular mechanisms has greatly facilitated creation proteins or pathways‐specific inhibitors advance precise therapy boost effectiveness radiotherapy. architectures, roles, processes, target reviewed this article. strategy application also discussed based advancement targeted response proteins.

Language: Английский

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