Understanding the Toxicity Profile of Approved ADCs

Pharmaceutics, Год журнала: 2025, Номер 17(2), С. 258 - 258

Опубликована: Фев. 14, 2025

Background: Antibody-drug conjugates (ADCs) represent a novel therapeutic class that combines an antibody against tumor-associated antigen (TAA), payload, and linker binds these two components. Serious adverse events (SAEs), particularly those of grade 3 (G3) or higher, frequently contribute to the abandonment ADCs during clinical development. Methods: In this study, we analyzed toxicity profiles all approved ADCs, aiming uncover correlations between their safety specific characteristics Results: our analysis, dose reductions, delays, treatment discontinuations, ≥G3 toxicities were not significantly different across payload types. Similarly, no association was found mechanism action toxicities, including anemia, neutropenia, febrile thrombocytopenia, diarrhea. By exploring observed by organ, identified most related action, like diarrhea in 10% patients treated with sacituzumab govitecan (the SN-38 is active metabolite irinotecan), very few presence TAA normal tissue (presence Nectin-4 skin rash 14% enfortumab vedotin). line this, major differences studies levels (trastuzumab deruxtecan Destiny Breast Studies HER2 expression levels). Conclusions: Our analysis reveals ADC are driven payload's effects on non-transformed tissues; however, detailed each component should be taken into consideration.

Язык: Английский

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Personalized Medicine in Pancreatic Cancer: The Promise of Biomarkers and Molecular Targeting with Dr. Michael J. Pishvaian

Cancers, Год журнала: 2024, Номер 16(13), С. 2329 - 2329

Опубликована: Июнь 26, 2024

Pancreatic cancer, with its alarming rising incidence, is predicted to become the second deadliest type of solid tumor by 2040, highlighting urgent need for improved diagnostic and treatment strategies. Despite medical advancements, five-year survival rate pancreatic cancer remains about 14%, dropping further when metastasized. This review explores promise biomarkers early detection, personalized treatment, disease monitoring. Molecular classification into subtypes based on genetic mutations, gene expression, protein markers guides decisions, potentially improving outcomes. A plethora clinical trials investigating different strategies are currently ongoing. Targeted therapies, among which those against CLAUDIN 18.2 inhibitors Claudin 18.1, have shown promise. Next-generation sequencing (NGS) has emerged as a powerful tool comprehensive genomic analysis tumors, revealing unique alterations that drive progression. allows oncologists tailor therapies target specific molecular abnormalities. However, challenges remain, including limited awareness uptake biomarker-guided therapies. Continued research mechanisms essential developing more effective treatments patient rates.

Язык: Английский

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Advances in Novel Targeted Therapies for Pancreatic Adenocarcinoma

Journal of Gastrointestinal Cancer, Год журнала: 2025, Номер 56(1)

Опубликована: Янв. 6, 2025

Язык: Английский

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MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 6, 2025

Homozygous MTAP deletion occurs in ~15% of cancers, making them vulnerable to decreases the concentration S-adenosylmethionine (SAM). AG-270/S095033 is an oral, potent, reversible inhibitor methionine adenosyltransferase 2 A (MAT2A), enzyme primarily responsible for synthesis SAM. We report results from first-in-human, phase 1 trial as monotherapy patients with advanced malignancies (ClinicalTrials.gov Identifier: NCT03435250). Eligible had tumors homozygous CDKN2A/MTAP and/or loss protein by immunohistochemistry. Patients received once daily (QD) or twice (BID) 28-day cycles. The primary objective was assess maximum tolerated dose (MTD) AG-270/S095033. Secondary objectives included safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Forty were treated Plasma concentrations increased dose. Maximal reductions plasma SAM ranged 54% 70%. Analysis paired tumor biopsies showed levels symmetrically di-methylated arginine (SDMA) residues. Reversible increases liver function tests, thrombocytopenia, anemia fatigue common treatment-related toxicities. Two partial responses observed; five additional achieved radiographically confirmed stable disease ≥16 weeks. has a manageable safety profile. Our data provide preliminary evidence clinical activity proof-of-mechanism MAT2A inhibition. AG-270 inhibited reduced up 70% solid tumors. Partial observed two stabilization ≥4 months seen patients.

Язык: Английский

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Discovery of Novel Spirocyclic MAT2A Inhibitors Demonstrating High In Vivo Efficacy in MTAP-Null Xenograft Models

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 21, 2025

Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit homozygous deletion S-methyl-5'-thioadenosine phosphorylase (MTAP). Herein, we report identification novel inhibitors featuring spiral ring to circumvent C-N atropisomeric chirality utilizing structure-based drug design. The Hit compound 9 exhibited high potency enzymatic activity (IC50 = 7 nM) and HCT-116 MTAP(-/-) cell 17 nM). Further optimization has led two new lead compounds: brain-penetrant compound, 29-1, potent but limited 39. Both these compounds demonstrate increased plasma exposure significant efficacy xenograft models are depleted MTAP. We hope identifying inhibitor will create opportunities explore potential therapeutic effects S-adenosylmethionine modulation central nervous system.

Язык: Английский

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Deficiency of MTAP Is Frequent and Mostly Homogeneous in Pancreatic Ductal Adenocarcinomas

Cancers, Год журнала: 2025, Номер 17(7), С. 1205 - 1205

Опубликована: Апрель 1, 2025

The complete loss of S-methyl-5'-thioadenosine phosphorylase (MTAP) expression, often due to homozygous 9p21 deletion, creates a druggable vulnerability in cancer cells. A total 769 primary pancreatic ductal adenocarcinomas were analyzed on tissue microarrays with MTAP immunohistochemistry (IHC) and fluorescence situ hybridization (FISH). Intratumoral heterogeneity was assessed "heterogeneity" TMA containing up nine samples from different areas 236 tumor nodal metastases, whole sections all blocks 19 cancers. expression found 181 (37.9%) 478 interpretable tumors unrelated pT, pN, grade, size. homogenous 37.6% heterogeneous 1.1% the tumors, at least three evaluable TMA. On sections, 1 showed loss. correlation between IHC FISH nearly perfect, 98.8% MTAP-deficient showing deletion. is frequent, caused by mostly homogeneous adenocarcinomas. Considering also their aggressive clinical behavior, may represent an ideal type for studying new drugs targeting cells trials.

Язык: Английский

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Perspectives on cancer therapy—synthetic lethal precision medicine strategies, molecular mechanisms, therapeutic targets and current technical challenges

Cell Death Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Апрель 16, 2025

Abstract In recent years, synthetic lethality has become an important theme in the field of targeted cancer therapy. Synthetic refers to simultaneous defects two or more genes leading cell death, whereas any single gene do not lead death. Taking advantage genetic vulnerability that exists within cells, it theoretically no negative impact on healthy cells and fewer side effects than non-specific chemotherapy. Currently, therapies focus inhibiting key pathways cancer. However, been found over-activation oncogenic-related signaling can also induce which is a major breakthrough new therapies. this review, we summarize conventional targets (PARP, ATR, ATM, WEE1, PRMT) provide in-depth analysis their latest potential mechanisms. We explore such as PI3K/AKT, MAPK, WNT survival, present technical challenges current research. Important theoretical foundations insights are provided for application lethal strategies therapy, well future research directions.

Язык: Английский

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Disrupting YAP1-mediated glutamine metabolism induces synthetic lethality alongside ODC1 inhibition in osteosarcoma

Cellular Oncology, Год журнала: 2024, Номер 47(5), С. 1845 - 1861

Опубликована: Авг. 8, 2024

Язык: Английский

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Prevalence of S-methyl-5′-thioadenosine Phosphorylase (MTAP) Deficiency in Human Cancer

The American Journal of Surgical Pathology, Год журнала: 2024, Номер 48(10), С. 1245 - 1258

Опубликована: Авг. 12, 2024

Loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression is a common event in cancer leading to critical vulnerability cells towards anti-cancer drugs. Homozygous MTAP deletions result complete loss that can be detected by immunohistochemistry (IHC). In this study, tissue microarray containing 17,078 samples from 149 different tumor entities was analyzed IHC, and validated fluorescence situ hybridization. observed 83 categories, including neuroendocrine neoplasms (up 80%), Hodgkin lymphoma (50.0%), mesothelioma (32.0% 36.8%), gastro-intestinal adenocarcinoma (4.0% 40.5%), urothelial (10.5% 36.7%), squamous cell carcinomas 38%), various types sarcomas 20%) non-Hodgkin lymphomas 14%). deletion found 90% 100% cases with most categories. However, tumors, lymphomas, other lacked deletions. deficiency significantly linked unfavorable phenotype selected the presence PD-L1 on cells, absence immune low density CD8 + lymphocytes. summary, occur noninflamed microenvironment, but not always related IHC considerable diagnostic value for detection neoplastic transformation multiple applications.

Язык: Английский

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MAT2A inhibition combats metabolic and transcriptional reprogramming in cancer

Drug Discovery Today, Год журнала: 2024, Номер 29(11), С. 104189 - 104189

Опубликована: Сен. 20, 2024

Язык: Английский

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