Mechanism-based cancer therapy: resistance to therapy, therapy for resistance

Ramos, Pedro Marques; Bentires‐Alj, Mohamed

doi:10.1038/onc.2014.314

Cited by 214 publications

(159 citation statements)

References 132 publications

(185 reference statements)

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“…Researchers have scrutinized the altered signaling pathways in malignant cells in hopes of finding the key protein conserved in oncogenesis and metastasis but that plays minimal role in normal cells [12]. However, these drugs are rarely as efficacious in the clinic, where de novo and emergent drug resistance is common [13].…”

Section: Emerging View Of Cancer As a Systemmentioning

confidence: 99%

A Quantitative Systems Pharmacology Perspective on Cancer Immunology

Byrne-Hoffman

Klinke

2015

Processes

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Abstract:The return on investment within the pharmaceutical industry has exhibited an exponential decline over the last several decades. Contemporary analysis suggests that the rate-limiting step associated with the drug discovery and development process is our limited understanding of the disease pathophysiology in humans that is targeted by a drug. Similar to other industries, mechanistic modeling and simulation has been proposed as an enabling quantitative tool to help address this problem. Moreover, immunotherapies are transforming the clinical treatment of cure cancer and are becoming a major segment of the pharmaceutical research and development pipeline. As the clinical benefit of these immunotherapies seems to be limited to subset of the patient population, identifying the specific defect in the complex network of interactions associated with host immunity to a malignancy is a major challenge for expanding the clinical benefit. Understanding the interaction between malignant and immune cells is inherently a systems problem, where an engineering perspective may be helpful. The objective of this manuscript is to summarize this quantitative systems perspective, particularly with respect to developing immunotherapies for the treatment of cancer. OPEN ACCESSProcesses 2015, 3 236

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Section: Emerging View Of Cancer As a Systemmentioning

confidence: 99%

A Quantitative Systems Pharmacology Perspective on Cancer Immunology

Byrne-Hoffman

Klinke

2015

Processes

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“…Of the various chemotherapy drugs available, cisplatin and 5-fluorouracil (5-FU) are the two most frequently utilized for the treatment of oral cancer (5). However, the efficacy of cancer chemotherapy is often limited by the development of drug resistance by the cancer cells in clinical practice (6).…”

Section: Introductionmentioning

confidence: 99%

Enhancing chemosensitivity in oral squamous cell carcinoma by lentivirus vector-mediated RNA interference targeting EGFR and MRP2

Chen

Lovel

et al. 2016

Oncology Letters

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Abstract. Oral cancer is the eighth most common type of cancer among men worldwide, with an age-standardized rate of 6.3 per 100,000, and is the fourth leading cause of cancer-associated mortality among men in Taiwan. Cisplatin and 5-fluorouracil (5-FU) are two of the most frequently utilized chemotherapy drugs for the treatment of oral cancer. Although oral cancer patients initially benefit from chemotherapy with these drugs, they may develop resistance to them, which worsens their prognosis and reduces survival rates. It has been reported that increased levels of epidermal growth factor receptor (EGFR) and multidrug resistance-associated protein 2 (MRP2) induce drug resistance in numerous types of human cancer. Therefore, the present study employed lentivirus vector-mediated RNA interference (RNAi) in order to target the genes encoding EGFR and MRP2 in the oral squamous cell carcinoma cell line OC2. It was observed that RNAi-mediated downregulation of EGFR or MRP2 increased the sensitivity to 5-FU and cisplatin in OC2 cells. Downregulation of EGFR resulted in significant suppression of OC2 tumor growth following 5-FU administration. However, simultaneous downregulation of the two genes did not further suppress the tumor growth, indicating that MRP2 does not have a significant role in the chemosensitivity of EGFR-downregulated cells to 5-FU. In contrast, downregulation of MRP2 was demonstrated to significantly enhance the therapeutic effects of cisplatin in EGFR-downregulated OC2 tumors. The observation that the expression of MRP2 was positively correlated with the level of cisplatin resistance in cells suggests that RNAi-mediated downregulation of MRP2 may be applicable as a therapeutic approach toward reversing MRP2-dependent cisplatin resistance in oral cancer. IntroductionOral cancer is the eighth most common type of cancer among men worldwide, with an age-standardized rate of 6.3 per 100,000 (1,2), and is the fourth leading cause of cancer-associated mortality among men in Taiwan (3). In addition, oral cancer has been ranked highest with respect to the rates of incidence and mortality among men aged 25-44 years in Taiwan since 2005 (3). Chemotherapy has been used as the primary treatment for patients exhibiting recurrent or metastatic cancers, including oral cancer (4). Of the various chemotherapy drugs available, cisplatin and 5-fluorouracil (5-FU) are the two most frequently utilized for the treatment of oral cancer (5). However, the efficacy of cancer chemotherapy is often limited by the development of drug resistance by the cancer cells in clinical practice (6).It has been demonstrated that multidrug resistance results largely from the expression of adenosine triphosphate-binding cassette (ABC) transporters with broad drug specificity (7-9). Multidrug resistance-associated protein 2 (MRP2), a member of the ABC transporter superfamily, has been observed in various tumors to confer resistance to a number of therapeutic drugs, including cisplatin (10-12). The levels of MRP2 messenger (m)RNA in certain hum...

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“…The distinct TME attributes within a given tumor select for mutations that allow survival, expansion and repopulation of cancer cells, while significantly creating tumor heterogeneity. Such a plasticity promotes the development of drug resistance through several mechanisms, including mutations of the target genes, reactivation of the targeted pathways, and cancer cross talk with the surrounding TME, with the latter largely overlooked in the past decades [3]. Besides, mounting data support that stromal cells, either naïve or therapeutically damaged, can produce and secrete a large group of soluble factors into the TME milieu, which act as critical signals delivered in a paracrine fashion and dramatically confer therapeutic resistance on cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Updated Landscape of the Tumor Microenvironment and Targeting Strategies in an Era of Precision Medicine

Sun¹,

Chiao²

2017

Patient Centered Medicine

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Despite successive advances in clinical diagnosis and therapeutic intervention, cancerassociated morbidity and mortality keeps up with escalating cost to human society. Clinicians are confronted with an unprecedented challenge in curing cancers with de novo or acquired resistance. Failure to achieve effective and long-lasting treatment effects arises from the complexity of malignancies, particularly when plasticity of cancer cells is coupled with survival adaptability conferred by the pathologically co-opted stroma in the tumor microenvironment (TME). Targeting immune checkpoints, such as programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA4), provide significant benefit in multiple tumor types and produce substantial anticancer responses. Tissue resident stromal cells, although damaged together with cancer cells upon cytotoxic treatments, represent an everreplenishing source that contributes to tumor restoration from residual cancer cells in the post-therapy stage. The TME displays a continually changing landscape, generating significant impacts on treatment outcome in clinics. Moving forward, implementing patient-specific analysis in clinical oncology with TME-oriented agents will significantly improve the specificity and efficacy of targeted therapies, thereby accelerating the translation of novel conceptions and groundbreaking discoveries in the TME biology through multiple bench-to-bed pipelines in current settings of precision cancer medicine.

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Mechanism-based cancer therapy: resistance to therapy, therapy for resistance

Cited by 214 publications

References 132 publications

A Quantitative Systems Pharmacology Perspective on Cancer Immunology

A Quantitative Systems Pharmacology Perspective on Cancer Immunology

Enhancing chemosensitivity in oral squamous cell carcinoma by lentivirus vector-mediated RNA interference targeting EGFR and MRP2

Updated Landscape of the Tumor Microenvironment and Targeting Strategies in an Era of Precision Medicine

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