Lapatinib Ditosylate Hydrate

A study has identified a biological mechanism that could lead to more effective treatments for breast cancer that has metastasized to the brain. A study led by researchers from the University of Arizona Cancer Center at UArizona Health Sciences identified a biological mechanism that could lead to more effective treatments for breast cancer that has metastasized to the brain. By studying the metabolic differences between primary breast cancer cells and those that metastasize to the brain, they determined that autophagy was significantly upregulated in brain metastases. Autophagy is a cellular recycling process that cancer cells can use to stay alive when faced with stressful conditions such as those triggered by anticancer drugs. "The prognosis for individuals with brain metastases from breast cancer is extremely unfavorable, and the management of breast cancer metastases in the brain remains a formidable challenge," said senior author Jennifer Carew, PhD. "We were able to disrupt breast cancer cells' ability to form brain metastases by impairing the autophagy pathway." In the study published in Clinical and Translational Medicine, the researchers first showed that targeting the key autophagy regulating gene ATG7 significantly reduced the ability of breast cancer cells to form brain metastases in mouse models. With the goal of developing a strategy to bring this discovery to patients, the research team investigated whether hydroxychloroquine, a Food and Drug Administration-approved drug, could potentially be used to treat breast cancer brain metastases. Hydroxychloroquine inhibits autophagy at a later point in the pathway and, importantly, readily crosses the blood-brain barrier. "Most drugs do not efficiently cross the blood-brain barrier, and that is one of the key reasons why brain metastases are so difficult to treat," said Carew, who is a professor of medicine at the UArizona College of Medicine -- Tucson and a member of the UArizona Cancer Center Clinical and Translational Oncology Program. The research team combined hydroxychloroquine with lapatinib, which is FDA-approved to treat breast cancer. They showed that this drug combination successfully reduced the number and size of breast cancer brain metastases in mouse models. Hydroxychloroquine has been combined with a number of other anticancer agents in early phase clinical trials, but this is the first time researchers have studied its effectiveness when combined with lapatinib for breast cancer therapy. Carew said the team was amazed by how significantly they were able to diminish the ability of breast cancer cells to form brain metastases by targeting a single pathway. "Cancer cells, unfortunately, have evolved so many ways that make it difficult for us to stop their growth or kill them," Carew said. "It is always somewhat surprising when you see how changing only one thing can have an impact." "Our group and others have shown that activation of autophagy makes it harder for many different types of cancer therapies to kill cancer cells and this promotes drug resistance," said first author Steffan Nawrocki, PhD, co-director of the Cancer Center Clinical and Translational Oncology Program and professor in the UArizona College of Medicine -- Tucson. "Because hydroxychloroquine and lapatinib are already FDA approved, we can advance this drug combination quickly into a clinical trial for patients with breast cancer brain metastases." Brain metastases are the most prevalent adult central nervous system tumors, with 20% to 30% of cases resulting from breast cancer patients, particularly those with triple negative and HER2 amplified disease. Managing breast cancer metastases in the brain is challenging, with only 20% of patients with breast cancer brain metastases surviving beyond five years. Other co-authors include Wei Wang, PhD, professor in the R. Ken Coit College of Pharmacy; former doctoral student Trace M. Jones, PhD; Claudia M. Espitia, assistant staff scientist in the College of Medicine -- Tucson; postdoctoral fellow Maria Janina Carrera Espinoza, PhD; and doctoral students Madison E. Gamble, Sruthi Sureshkumar and Mengyang Chang. This research was supported by the National Cancer Institute, a division of the National Institutes of Health, under Award Nos. T32CA009213, R21CA184649, R01CA190789, R01CA268383 and P30CA023074.

Results published by the DETECT study group indicate the relevance of assessing biomarker expression in Circulating Tumor Cells (CTCs) with the minimally invasive liquid biopsy-based CELLSEARCH® platform to optimize treatment strategy and outcome in patients at an advanced stage of their disease. BOLOGNA, Italy and HUNTINGDON VALLEY, Pa., Jan. 9, 2024 /PRNewswire/ -- Menarini Silicon Biosystems, a pioneer of liquid biopsy technology, announced today the publication, in the Journal of Clinical Chemistry, of the final results of the multicenter DETECT III clinical trial. This, interventional, investigator-initiated, phase III trial evaluated the efficacy of HER2-targeted therapy in metastatic breast cancer patients with HER2 negative tissue biopsy of the primary and/or metastatic site and HER2 positive CTCs detected with the CELLSEARCH system. Patients randomized to the treatment arm with reference HER2-targeted TKI (Tyrosine Kinase Inhibitor) lapatinib, in addition to standard therapy, showed greater overall survival (OS) over patients treated with standard therapy alone. This allowed physicians to consider early initiation of HER2-targeted therapy. Based on the primary tumor and/or metastatic site characteristics and the current standard of care, those patients would not have been eligible for HER2 targeted therapy. According to Prof. Dr. med. Wolfgang Janni, MD, PhD, Professor and Chair of the Department of Obstetrics and Gynecology at the University of Ulm, Germany, study director of the DETECT III trial: "the results of this trial suggest the potential of CTCs as noninvasive surrogates for invasive tissue-based biomarkers, as well as an early monitoring tool. CTC phenotyping could contribute to personalized treatment approaches that allow us to improve management of patients with advanced disease and discordant expression of the HER2 receptor". A total of 2,137 patients with HER2 negative MBC were screened for HER2 positive CTCs using Menarini Silicon Biosystems' CELLSEARCH® CTC System and the CELLSEARCH HER2 tumor phenotyping reagent*. 105 patients, with at least one detected HER2 positive CTC in the initial CTC screening phase, were randomized to either lapatinib in combination with standard therapy or to standard therapy alone. Patients in the lapatinib arm had a significantly improved OS with a median survival time of 20.5 months compared to a median survival time of 9.1 months for patients in the standard arm (HR 0.54; 95% CI 0.34–0.86; p = 0.008). While investigators acknowledge some limitations in the study design, the results indicate that CTC-guided treatment allocation may help optimize treatment strategies and should therefore be further investigated. The study also confirmed the prognostic role of CELLSEARCH CTC enumeration. Patients with no evidence of CTCs at the time of first follow-up showed a 3-fold increase in OS compared to patients with CTCs (42.4 months vs 14.1 months median OS; HR 0.33; 95% CI 0.16–0.68; p = 0.002) "We are thrilled by the fact that the DETECT III study provides additional data further elucidating the potential value of our minimally invasive CELLSEARCH technology," said Fabio Piazzalunga, President of Menarini Silicon Biosystems. "This study is another example of why we are so committed to pursuing our investments in the CELLSEARCH platform in different cancer settings." About the DETECT study program DETECT is the largest study program utilizing Circulating Tumor Cell (CTC) count and HER2 phenotype assessment to personalize treatment strategies for HER2 negative MBC. The aim of this protocol was to evaluate the impact of adapting therapeutic interventions based on CTC phenotypes in patients with a discordant HER2 negative primary tumor biopsy and HER2+ over expression of CTCs in the metastatic setting. The study results consistently show the importance of adding HER2 targeted therapy in this patient population to improve long-term clinical outcomes. About CELLSEARCH CELLSEARCH is the first and only clinically validated blood test cleared by the U.S. Food & Drug Administration (FDA) for detecting and counting CTCs to aid physicians in managing patients with metastatic breast, prostate, and colorectal cancers when used in conjunction with other clinical methods of monitoring. The test is also approved by the China National Medical Products Administration (NMPA) for use in monitoring patients with Metastatic Breast Cancer. The CELLSEARCH System is the most extensively studied CTC technology, with research published in more than 650 peer-reviewed publications. CELLSEARCH Circulating Tumor Cell Kit is not cleared or approved for use to guide specific treatment decisions. For more information on the full intended use and limitations of the CELLSEARCH system, please refer to the Instructions for Use at . The CELLSEARCH HER2 tumor phenotyping reagent is available as a Research Use Only product in Europe and Asia Pacific. In the USA only, the CELLSEARCH CTC test with HER2 biomarker is available to clinicians, through Menarini Silicon Biosystems' CLIA registered clinical laboratory as a laboratory developed test. About Menarini Silicon Biosystems Menarini Silicon Biosystems offers unique rare cell technologies and solutions that provide clinical researchers with access to unparalleled resolution in the study of cells and their molecular characterization. Menarini Silicon Biosystems, based in Bologna, Italy, and Huntingdon Valley, Pa., U.S., is a wholly owned subsidiary of the Menarini Group, a multinational pharmaceutical, biotechnology and diagnostics company headquartered in Florence, Italy, with more than 17,000 employees in 140 countries. * The CELLSEARCH® Tumor Phenotyping Reagent (HER-2/neu) is available for Research Use Only. Not for Use in Diagnostic Procedures. CONTACT: Linda PAVY – lipavy@pavyconsulting.com Logo - View original content: SOURCE Menarini Silicon Biosystems