Article
Engineering, Biomedical
Ri Huang, Hong Du, Liang Cheng, Peizhuo Zhang, Fenghua Meng, Zhiyuan Zhong
Summary: In this study, cRGD peptide-modified bioresponsive chimaeric polymersomes (cRGD-BCP) were used for efficient delivery of siKRAS to PANC-1 tumor cells, resulting in potent silencing of KRAS G12D mRNA and effective suppression of pancreatic cancer tumor growth in mice. The density of cRGD greatly impacted the uptake and silencing efficiency of cRGD-BCP-siKRAS. cRGD-BCP-siKRAS significantly enhanced the uptake of siKRAS in PANC-1 tumor and achieved remarkable tumor inhibition and survival benefits.
ACTA BIOMATERIALIA
(2023)
Review
Oncology
Sahar F. Bannoura, Husain Yar Khan, Asfar S. Azmi
Summary: KRAS mutations are common in cancer, and recent advancements have shown that small molecule inhibitors can be developed against KRAS G12C, although there is still no agent to target KRAS G12D. However, significant progress has been made in developing compounds that can bind to and inhibit KRAS G12D, including MRTX1133. Additionally, an immunotherapeutic approach using adoptive T-cell transfer has shown promise in targeting G12D in pancreatic cancer.
FRONTIERS IN ONCOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Shubaash Anthiya, Suleyman Can Ozturk, Hamdullah Yanik, Ece Tavukcuoglu, Adem Sahin, Dhrubajyoti Datta, Klaus Charisse, David Moreira Alvarez, Maria Isabel Loza, Alfonso Calvo, Einar Sulheim, Simon Loevenich, Geir Klinkenberg, Ruth Schmid, Muthiah Manoharan, Gunes Esendagli, Maria Jose Alonso
Summary: The aim of this study was to develop a new therapeutic strategy for anti-KRAS siRNA through functionalized lipid nanoparticles (LNPs). A potent anti-KRAS siRNA sequence was chosen and tested for transfection efficacy and anti-proliferative effects. The selected siRNA was loaded into targeted and non-targeted LNPs, and their biodistribution and antitumoral efficacy were evaluated in a pancreatic cancer murine model. The results showed enhanced tumor accumulation and significant reduction in tumor growth with the targeted LNPs.
JOURNAL OF CONTROLLED RELEASE
(2023)
Review
Health Care Sciences & Services
Darren Cowzer, Mohammed Zameer, Michael Conroy, Walter Kolch, Austin G. Duffy
Summary: This article reviews therapeutic innovations targeting RAS signaling in pancreatic cancer from a clinical perspective. Despite the strong resistance of pancreatic cancer to treatment, new approaches such as inhibiting mutated KRAS, KRAS activators, and effectors show promise in breaking this therapeutic deadlock.
JOURNAL OF PERSONALIZED MEDICINE
(2022)
Review
Medicine, General & Internal
Andres Garcia-Sampedro, Gabriella Gaggia, Alexander Ney, Ismahan Mahamed, Pilar Acedo
Summary: Pancreatic cancer has a poor prognosis, and surgery with adjuvant chemotherapy is the only curative option for a small group of patients. Novel therapeutic strategies are urgently needed for advanced or metastatic cases where surgical resection is not possible. Molecular profiling and targeted therapies show promise in overcoming the limitations of conventional treatments. Currently, personalized and multimodal targeted therapies are undergoing clinical trials with promising results targeting various aspects of pancreatic cancer.
JOURNAL OF CLINICAL MEDICINE
(2021)
Article
Medicine, Research & Experimental
Fang Yuan, Mengnan Sun, Zhengsheng Liu, Huiqin Liu, Weijian Kong, Rui Wang, Feng Qian
Summary: Pancreatic cancer cells with high levels of macropinocytosis can be targeted using macropinocytic dextran as a delivery carrier. Conjugating triptolide with 70 kDa dextran enhances the therapeutic effects on KRAS mutant cells and preserves immune factors, reducing the impact on T cells.
Article
Medicine, General & Internal
J. H. Strickler, H. Satake, T. J. George, R. Yaeger, A. Hollebecque, I Garrido-Laguna, M. Schuler, T. F. Burns, A. L. Coveler, G. S. Falchook, M. Vincent, Y. Sunakawa, L. Dahan, D. Bajor, S-Y Rha, C. Lemech, D. Juric, M. Rehn, G. Ngarmchamnanrith, P. Jafarinasabian, Q. Tran, D. S. Hong
Summary: This study evaluated the safety and efficacy of sotorasib in patients with KRAS p.G12C-mutated pancreatic cancer who had previously received treatment. The results showed that sotorasib demonstrated anticancer activity and had an acceptable safety profile in these patients.
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Review
Critical Care Medicine
David F. Condon, Stuti Agarwal, Ananya Chakraborty, Natasha Auer, Rocio Vazquez, Hirai Patel, Roham T. Zamanian, Vinicio A. de Jesus Perez
Summary: Pulmonary arterial hypertension (PAH) is a rare disease characterized by abnormally elevated pulmonary pressures and right heart failure, resulting in high morbidity and mortality. Current therapies are insufficient in preventing small-vessel loss and obstruction, leading to active interest in identifying drugs that target angiogenesis and mechanisms involved in cell growth and fibrosis regulation. Preclinical studies have identified promising compounds that target seven major mechanisms associated with PAH pathogenesis, including bone morphogenetic protein signaling, tyrosine kinase receptors, estrogen metabolism, extracellular matrix, angiogenesis, epigenetics, and serotonin metabolism. This review discusses the prioritization of these mechanisms through preclinical studies, as well as ongoing clinical trials testing novel interventions. The authors anticipate that the next generation of compounds will build upon the current standard of care and improve clinical outcomes and quality of life for PAH patients.
Review
Biochemistry & Molecular Biology
Fernand Bteich, Mahshid Mohammadi, Terence Li, Muzaffer Ahmed Bhat, Amalia Sofianidi, Ning Wei, Chaoyuan Kuang
Summary: Colorectal cancer is a heterogeneous disease with various alterations at the cellular and molecular levels. KRAS mutations are found in up to 40% of CRCs and serve as both a prognostic and predictive biomarker. Targeting KRAS mutations in CRC is being explored through both indirect and direct strategies, with several KRAS allele-specific inhibitors in late-phase clinical trials and newer agents and targeting strategies undergoing preclinical and early-phase clinical testing.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Joanne Lundy, Hugh Gao, William Berry, Samar Masoumi-Moghoddam, Brendan J. Jenkins, Daniel Croagh
Summary: This study investigated the potential of combining transcriptomic and mutation analysis with standard cytology to improve the accuracy of PDAC diagnosis and identified an effective diagnostic gene signature. KRAS mutation analysis significantly improved diagnostic accuracy to 91.3% in external validation sets and 91.6% in the validation cohort. Additionally, exploratory analysis suggested that KRAS mutant allele fraction may serve as a novel surrogate marker of tumor cellularity in snap-frozen EUS-FNA biopsies.
CLINICAL CANCER RESEARCH
(2021)
Article
Immunology
W. Watson Buchanan, Colin A. Kean, K. D. Rainsford, Walter F. Kean
Summary: A clinical trial is a research method that investigates the therapeutic intervention's efficacy, both short-term and long-lasting, as well as its potential toxicity. The history of clinical trials can be traced back to Babylonian King Nebuchadnezzar's court around 600 BC, as described in the Book of Daniel. However, it is in the past 500 years that significant written documentation and interpretation of therapeutic benefits have been made. Examples such as Lind's demonstration on the effectiveness of oranges and lemons for scurvy treatment in 1747, and Edward Jenner's unethical experiment on inoculation in 1796, showcase the importance of clinical trials. Ethical considerations, rigorous clinical observations, statistics, scientific purity of therapeutic agents, and safety testing have contributed to the foundation of modern clinical trials.
INFLAMMOPHARMACOLOGY
(2023)
Editorial Material
Medicine, General & Internal
Cornelis J. M. Melief
Summary: Pancreatic ductal adenocarcinoma is the deadliest of all common cancers. The study reported remarkable deep and durable tumor shrinkage in a heavily pretreated patient who received an infusion of autologous T cells transduced.
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Review
Chemistry, Multidisciplinary
Bethany M. Cooper, Jessica Iegre, Daniel H. O' Donovan, Maria Olwegard Halvarsson, David R. Spring
Summary: Peptides offer versatility in oncology drug discovery, with peptide-drug conjugates showing promise in targeting tumors. Despite limitations such as slow progress and limited oral bioavailability, new approaches have enhanced peptide stability, leading to two molecules on the market and various variations in clinical trials.
CHEMICAL SOCIETY REVIEWS
(2021)
Review
Pharmacology & Pharmacy
Zhiyi Zhang, Jie Song, Cao Xie, Jun Pan, Weiyue Lu, Min Liu
Summary: Pancreatic cancer is a highly malignant tumor that is difficult to diagnose early, with most patients diagnosed in advanced stages. Current main treatments include chemotherapy, which has not significantly improved patient prognosis.
Article
Biochemistry & Molecular Biology
Diego Alem, Xinrui Yang, Francisca Beato, Bhaswati Sarcar, Alexandra F. Tassielli, Ruifan Dai, Tara L. Hogenson, Margaret A. Park, Kun Jiang, Jianfeng Cai, Yu Yuan, Martin E. Fernandez-Zapico, Aik Choon Tan, Jason B. Fleming, Hao Xie
Summary: Targeting mutant KRAS (mKRAS) in colorectal cancer (CRC) and other malignancies has been challenging. Recent efforts have focused on developing inhibitors blocking molecules essential for KRAS activity, with SOS1 inhibition emerging as an attractive approach for mKRAS CRC. In this study, CRC patient-derived organoids (PDOs) were used to evaluate the sensitivity to SOS1 inhibitor BI3406, and potential predictive markers and resistance mechanisms were identified.
MOLECULAR CARCINOGENESIS
(2023)