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A Semi-Quantitative Drug Affinity Responsive Target Stability (DARTS) assay for studying Rapamycin/mTOR interaction
Published on: August 27, 2019
Mammalian target of rapamycin
Funda Meric-Bernstam1, Gordon B Mills
1University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
Targeted molecular therapeutics are tailored toward the genetic abnormalities that cause tumor progression. Modulation of certain signaling pathways that are aberrant in cancer cells has the potential to provide an effective, nontoxic approach to therapy in a broad range of cancers. Agents targeting BCR-ABL (imatinib mesylate [formerly known as STI-571], Gleevec; Novartis Pharmaceuticals Corp, East Hanover, NJ), retinoid receptor fusion proteins (all-trans retinoic acid), ErbB-2 or HER2/neu (trastuzumab, Herceptin; Genentech, Inc, South San Francisco, CA), epidermal growth factor receptor (IMC-C225 and ZD1839), and the phosphatidylinositol 3-kinase pathway (CCI-779) have all induced remarkable, nontoxic responses in a subset of patients with cancer and abnormalities in the corresponding signal transduction cascades. To achieve successful individualized therapy, the specific components within the aberrant signaling pathways that are driving the pathophysiology of the tumors must be identified in each patient. Molecular diagnostics can identify patients in whom the target is aberrant; linking molecular diagnostics with effective molecular therapeutics will be necessary to translate these concepts into approaches that will alter the outcome for patients with cancer. In addition, intermediary markers and/or molecular imaging techniques must be used to identify the biologically relevant dose that is sufficient to inhibit the target of interest. This review focuses on the P13K pathway, and novel molecules targeting this pathway, to illustrate the questions and challenges underlying the implementation of molecular therapeutics in breast and ovarian cancer.
Insights
Targeted molecular therapies offer a promising, non-toxic approach to cancer treatment by targeting specific genetic abnormalities. Linking molecular diagnostics with these advanced therapeutics is crucial for effective individualized cancer care.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Targeted molecular therapeutics exploit genetic abnormalities driving cancer progression.
- Modulating aberrant signaling pathways in cancer cells presents a potential non-toxic therapy.
- Several targeted agents have shown remarkable responses in specific patient subsets.
Purpose of the Study:
- To review novel molecules targeting the phosphatidylinositol 3-kinase (PI3K) pathway.
- To illustrate challenges in implementing molecular therapeutics for breast and ovarian cancers.
- To emphasize the need for identifying specific aberrant pathway components for individualized therapy.
Main Methods:
- Review of existing literature on targeted molecular therapeutics.
- Focus on agents targeting BCR-ABL, retinoid receptors, HER2/neu, EGFR, and the PI3K pathway.
- Discussion of molecular diagnostics, intermediary markers, and molecular imaging.
Main Results:
- Targeted agents like imatinib, trastuzumab, and others have demonstrated efficacy in specific cancers.
- Molecular diagnostics are essential for identifying patients with aberrant targets.
- Intermediary markers and imaging are needed to determine biologically relevant drug doses.
Conclusions:
- Successful individualized cancer therapy requires identifying specific aberrant signaling pathway drivers.
- Integrating molecular diagnostics with molecular therapeutics is key to improving patient outcomes.
- The PI3K pathway and its targeted agents are a focus for advancing breast and ovarian cancer treatment.
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