22 research outputs found
Nuclear Basic Fibroblast Growth Factor Regulation of Triple-Negative Breast Cancer Dormancy/Recurrence
No full textChemotherapy remains the only available treatment for triple-negative (TN) breast cancer. Although some TN breast cancers respond initially to neoadjuvant chemotherapy, the majority of patients die within three years of treatment due to recurrent tumor growth. Developing ex vivo models for TN breast cancer recurrence and defining responsible molecules will be crucial to developing effective combination therapies for TN breast cancer patients. We have developed an in vitro model of TN breast cancer dormancy/recurrence. Short-term exposure of tumor cells to chemotherapy at clinically relevant doses enriches for a dormant tumor cell population. Several days after removing chemotherapy, dormant tumor cells regain proliferative ability and establish colonies, resembling tumor recurrence. Tumor cells from "recurrent" colonies exhibit increased chemotherapy resistance, resembling therapy resistance of recurrent tumors in patients. Furthermore, we identify a novel signaling axis [nuclear bFGF/DNA-dependent protein kinase (DNA-PK)] supported by chemotherapy-enriched dormant TN breast cancer cells. This signaling axis drives accelerated DNA repair in chemo-residual TN breast cancer cells. Targeting this axis with either with a bFGF shRNA or DNA-PK small molecule inhibitor blocks recurrent colony formation. Using the Oncomine gene expression database, we found that bFGF expression in tumor samples from TN breast cancer patients predicts five year tumor recurrence following neoadjuvant chemotherapy treatment. Finally, we demonstrate that recurrent tumor cells exhibit increased invasiveness, reflecting the aggressive behavior of recurrent tumors in patients. Collectively, these studies identify a novel signaling axis in TN breast cancer that likely contributes to tumor recurrence and provide molecular targets for developing future therapeutics against TN breast cancer.</p
Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer
No full textLung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type and is still incurable for most patients at the advanced stage. Targeted therapy is an effective treatment that has significantly improved survival in NSCLC patients with actionable mutations. However, therapy resistance occurs widely among patients leading to disease progression. In addition, many oncogenic driver mutations in NSCLC still lack targeted agents. New drugs are being developed and tested in clinical trials to overcome these challenges. This review aims to summarize emerging targeted therapy that have been conducted or initiated through first-in-human clinical trials in the past year
Emerging Immunotherapies for Advanced Non-Small-Cell Lung Cancer
No full textLung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, with nearly half of all patients diagnosed at an advanced stage. Immune checkpoint inhibitors (ICIs) harness the host immune system to combat malignant cells. ICIs, which target programmed death-ligand 1 (PD-L1), programmed cell death 1 (PD-1), and cytotoxic T-cell lymphocyte-4 (CTLA-4), have transformed the treatment landscape for advanced NSCLC. While a subset of patients experiences a long-term durable response, most patients will develop disease progression. New drugs targeting novel pathways are being tested in clinical trials to improve the efficacy of immunotherapy and overcome resistance patterns. This review aims to summarize the currently available ICIs for advanced NSCLC and describe emerging immunotherapies with recently published data from phase I/II clinical trials
A Three-Dimensional Optimization Framework for Asphalt Mixture Design: Balancing Skeleton Stability, Segregation Control, and Mechanical Strength
No full textThe composition design of asphalt mixtures plays a pivotal role in determining pavement performance and durability. To improve skeleton stability, paving uniformity, and mechanical strength, this research proposes a three-dimensional optimization framework for asphalt mixture design, focusing on aggregate gradation and optimum asphalt content. A skeleton-dense and anti-segregation gradation optimization method was developed by integrating a previously established skeleton-dense model with a segregation tendency prediction approach. In parallel, a mechanically driven method for determining optimum asphalt content was proposed by introducing the maximum migration shear stress as a performance-based alternative to the conventional Marshall stability parameter. Research results show that asphalt mixtures designed and compacted with the optimized gradation exhibit significantly enhanced high-temperature stability, while maintaining satisfactory low-temperature cracking resistance and moisture susceptibility. Field validation was conducted through the construction of a trial pavement section using the optimized gradation under recommended mixing and compaction temperatures. The resulting pavement demonstrated excellent compaction, strong resistance to segregation, and a highly stable spatial structure. These findings confirm the effectiveness of the proposed methodology in enhancing the high-temperature deformation resistance and overall structural integrity of asphalt mixtures
Curative immunotherapy-based strategies for non-metastatic non-small cell lung cancer
No full textThe emergence of immunotherapy has ushered in a new era in the management of non-small cell lung cancer (NSCLC). Various immune check point inhibitors have demonstrated significant benefit in the management of locally advanced NSCLC that are treated with either surgery or concurrent chemoradiation. We provide a comprehensive and up-to-date review of data from key studies, discuss the challenging clinical issue regarding the timing and duration of immunotherapy in patients undergoing surgery, and highlight the unmet needs and future directions of immunotherapy in NSCLC
P2.01-056 Distinct PD-L1 Expression in Different Components of Pulmonary Sarcomatoid Carcinoma and Its Association with MET Mutation
No full textModel of tumor dormancy/recurrence after short-term chemotherapy.
No full textAlthough many tumors regress in response to neoadjuvant chemotherapy, residual tumor cells are detected in most cancer patients post-treatment. These residual tumor cells are thought to remain dormant for years before resuming growth, resulting in tumor recurrence. Considering that recurrent tumors are most often responsible for patient mortality, there exists an urgent need to study signaling pathways that drive tumor dormancy/recurrence. We have developed an in vitro model of tumor dormancy/recurrence. Short-term exposure of tumor cells (breast or prostate) to chemotherapy at clinically relevant doses enriches for a dormant tumor cell population. Several days after removing chemotherapy, dormant tumor cells regain proliferative ability and establish colonies, resembling tumor recurrence. Tumor cells from "recurrent" colonies exhibit increased chemotherapy resistance, similar to the therapy resistance of recurrent tumors in cancer patients. Previous studies using long-term chemotherapy selection models identified acquired mutations that drive tumor resistance. In contrast, our short term chemotherapy exposure model enriches for a slow-cycling, dormant, chemo-resistant tumor cell sub-population that can resume growth after drug removal. Studying unique signaling pathways in dormant tumor cells enriched by short-term chemotherapy treatment is expected to identify novel therapeutic targets for preventing tumor recurrence
mutations for personalized treatment of lung cancer patients without pathologic diagnosis
No full textNuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance
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