Precision Cardio-Oncology: Use of Mechanistic Pharmacokinetic and Pharmacodynamic Modeling to Predict Cardiotoxicities of Anti-Cancer Drugs

The cardiotoxicity of anti-cancer drugs presents as a challenge to both clinicians and patients. Significant advances in cancer treatments have improved patient survival rates, but have also led to the chronic effects of anti-cancer therapies becoming more prominent. Additionally, it is difficult to clinically predict the occurrence of cardiovascular toxicities given that they can be transient or irreversible, with large between-subject variabilities. Further, cardiotoxicities present a range of different symptoms and pathophysiological mechanisms. These notwithstanding, mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) modeling offers an important approach to predict cardiotoxicities and offering precise cardio-oncological care. Efforts have been made to integrate the structures of physiological and pharmacological networks into PK-PD modeling to the end of predicting cardiotoxicities based on clinical evaluation as well as individual variabilities, such as protein expression, and physiological changes under different disease states. Thus, this review aims to report recent progress in the use of PK-PD modeling to predict cardiovascular toxicities, as well as its application in anti-cancer therapies.

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microRNA: The Impact on Cancer Stemness and Therapeutic Resistance

Cells ◽

10.3390/cells9010008 ◽

2019 ◽

Vol 9 (1) ◽

pp. 8 ◽

Cited By ~ 6

Author(s):

Xueqiao Jiao ◽

Xianling Qian ◽

Longyuan Wu ◽

Bo Li ◽

Yi Wang ◽

...

Keyword(s):

Stem Cells ◽

Noncoding Rna ◽

Tumor Recurrence ◽

Tumor Promoter ◽

Therapeutic Resistance ◽

Cancer Therapies ◽

Cancer Treatments ◽

Small Noncoding Rna ◽

Anti Cancer ◽

The Impact

Cancer ranks as the second leading cause of death worldwide, causing a large social and economic burden. However, most anti-cancer treatments face the problems of tumor recurrence and metastasis. Therefore, finding an effective cure for cancer needs to be solved urgently. Recently, the discovery of cancer stem cells (CSCs) provides a new orientation for cancer research and therapy. CSCs share main characteristics with stem cells and are able to generate an entire tumor. Besides, CSCs usually escape from current anti-cancer therapies, which is partly responsible for tumor recurrence and poor prognosis. microRNAs (miRNAs) belong to small noncoding RNA and regulate gene post-transcriptional expression. The dysregulation of miRNAs leads to plenty of diseases, including cancer. The aberrant miRNA expression in CSCs enhances stemness maintenance. In this review, we summarize the role of miRNAs on CSCs in the eight most common cancers, hoping to bridge the research of miRNAs and CSCs with clinical applications. We found that miRNAs can act as tumor promoter or suppressor. The dysregulation of miRNAs enhances cell stemness and contributes to tumor metastasis and therapeutic resistance via the formation of feedback loops and constitutive activation of carcinogenic signaling pathways. More importantly, some miRNAs may be potential targets for diagnosis, prognosis, and cancer treatments.

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Exploring the Diversity of the Marine Environment for New Anti-cancer Compounds

Frontiers in Marine Science ◽

10.3389/fmars.2020.614766 ◽

2021 ◽

Vol 7 ◽

Author(s):

Divya L. Dayanidhi ◽

Beatrice C. Thomas ◽

Joshua S. Osterberg ◽

Mallissa Vuong ◽

Giselle Vargas ◽

...

Keyword(s):

Terrestrial Ecosystems ◽

Cancer Therapies ◽

Clinical Use ◽

Marine Environments ◽

Cancer Drugs ◽

Hallmarks Of Cancer ◽

Natural Sources ◽

Anti Cancer ◽

Almost All ◽

Untapped Resource

Marine ecosystems contain over 80% of the world’s biodiversity, and many of these organisms have evolved unique adaptations enabling survival in diverse and challenging environments. The biodiversity within the world’s oceans is a virtually untapped resource for the isolation and development of novel compounds, treatments, and solutions to combat human disease. In particular, while over half of our anti-cancer drugs are derived from natural sources, almost all of these are from terrestrial ecosystems. Yet, even from the limited analyses to date, a number of marine-derived anti-cancer compounds have been approved for clinical use, and several others are currently in clinical trials. Here, we review the current suite of marine-derived anti-cancer drugs, with a focus on how these compounds act upon the hallmarks of cancer. We highlight potential marine environments and species that could yield compounds with unique mechanisms. Continued exploration of marine environments, along with the characterization and screening of their inhabitants for unique bioactive chemicals, could prove fruitful in the hunt for novel anti-cancer therapies.

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The Complex Cancer Care Coverage Environment — What is the Role of Legislation?

The Journal of Law Medicine & Ethics ◽

10.1177/1073110520958879 ◽

2020 ◽

Vol 48 (3) ◽

pp. 538-551 ◽

Cited By ~ 1

Author(s):

Christine Leopold ◽

Rebecca L. Haffajee ◽

Christine Y. Lu ◽

Anita K. Wagner

Keyword(s):

Cancer Care ◽

Insurance Coverage ◽

Cancer Therapeutics ◽

Health Insurance Coverage ◽

Cancer Therapies ◽

Cancer Treatments ◽

Difficult Situation ◽

Cell Therapies ◽

State Laws ◽

Anti Cancer

Over the past decades, anti-cancer treatments have evolved rapidly from cytotoxic chemotherapies to targeted therapies including oral targeted medications and injectable immunooncology and cell therapies. New anti-cancer medications come to markets at increasingly high prices, and health insurance coverage is crucial for patient access to these therapies. State laws are intended to facilitate insurance coverage of anti-cancer therapies.Using Massachusetts as a case study, we identified five current cancer coverage state laws and interviewed experts on their perceptions of the relevance of the laws and how well they meet the current needs of cancer care given rapid changes in therapies. Interviewees emphasized that cancer therapies, as compared to many other therapeutic areas, are unique because insurance legislation targets their coverage. They identified the oral chemotherapy parity law as contributing to increasing treatment costs in commercial insurance. For commercial insurers, coverage mandates combined with the realities of new cancer medications — including high prices and often limited evidence of efficacy at approval — compound a difficult situation. Respondents recommended policy approaches to address this challenging coverage environment, including the implementation of closed formularies, the use of cost-effectiveness studies to guide coverage decisions, and the application of value-based pricing concepts. Given the evolution of cancer therapeutics, it may be time to evaluate the benefits and challenges of cancer coverage mandates.

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Timing of US Food and Drug Administration (FDA) cancer drug approvals relative to publication of clinical trial results.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.2071 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 2071-2071 ◽

Cited By ~ 1

Author(s):

Ali Raza Khaki ◽

Aakash Desai ◽

Martin W. Schoen ◽

Bishal Gyawali ◽

Eddy J. Chen ◽

...

Keyword(s):

Clinical Trial ◽

Cancer Drug ◽

Cancer Drugs ◽

Cancer Treatments ◽

Fda Approval ◽

Anti Cancer ◽

Accelerated Approval ◽

Drug Approvals ◽

Clinical Trial Results ◽

Careful Assessment

2071 Background: Publication of clinical trial results in peer reviewed literature is essential to inform clinicians regarding the use of new anti-cancer treatments, which often have a low therapeutic ratio and require careful assessment of risks and benefits. Publication of registration trials should precede FDA approval to facilitate evaluation and implementation of new therapies. The timing of trial publication relative to FDA drug approvals has not been systematically investigated. Methods: We collected all FDA drug approvals for a cancer indication between 2000-19. Trials were identified using FDA labels as well as drugs and publications indexed on HemOnc.org. Approvals for generics/biosimilars, non-oncology indications and label revisions without supportive evidence were excluded. Dates of approval, the approval pathway, approval type (new vs expansion), and the first full publication related to the registration were recorded. Trials and approvals were matched using available metadata. We calculated the proportion of drugs approved prior to publication overall and for those receiving accelerated approval (AA). We used logistic regression to compare rates of pre-publication approval by approval pathway and by new vs expanded approval. Results: Among a total of 378 drug approvals, 139 (37%) had pre-publication approval. Of these, the median overall time from approval to publication was 140 days (IQR 64-281 days). For those with approval after publication, median time from publication to approval was 157 days (IQR 72-359 days). The number of drugs approved pre-publication rose by 27% between the first and last quarters of the study period, though, the proportion decreased as more anti-cancer drugs have been approved in recent years (Table). More drugs were approved pre-publication through AA than regular approval (46% vs 34%, OR 1.66 [95% CI 1.03-2.70], p=0.04) and as new approvals vs. expanded approvals (45% vs 32%, OR 1.76 [95% CI 1.15-2.70], p=0.01). Conclusions: A substantial minority of FDA approvals occur before trial results are published, with the odds being higher for drugs receiving AA and for new approvals. Since clinicians rely upon published results to inform risk/benefit decisions, efforts are needed to ensure trial results are published by the time of FDA approval of new cancer drugs and indications. [Table: see text]

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Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature

Frontiers in Oncology ◽

10.3389/fonc.2020.612802 ◽

2021 ◽

Vol 10 ◽

Cited By ~ 2

Author(s):

Aukie Hooglugt ◽

Miesje M. van der Stoel ◽

Reinier A. Boon ◽

Stephan Huveneers

Keyword(s):

Tumor Microenvironment ◽

Tumor Metastasis ◽

Lymphatic Vessels ◽

Cancer Therapies ◽

Tumor Cell Growth ◽

Vascular Normalization ◽

Cancer Treatments ◽

Anti Cancer ◽

Tumor Endothelium

Solid tumors are dependent on vascularization for their growth. The hypoxic, stiff, and pro-angiogenic tumor microenvironment induces angiogenesis, giving rise to an immature, proliferative, and permeable vasculature. The tumor vessels promote tumor metastasis and complicate delivery of anti-cancer therapies. In many types of tumors, YAP/TAZ activation is correlated with increased levels of angiogenesis. In addition, endothelial YAP/TAZ activation is important for the formation of new blood and lymphatic vessels during development. Oncogenic activation of YAP/TAZ in tumor cell growth and invasion has been studied in great detail, however the role of YAP/TAZ within the tumor endothelium remains insufficiently understood, which complicates therapeutic strategies aimed at targeting YAP/TAZ in cancer. Here, we overview the upstream signals from the tumor microenvironment that control endothelial YAP/TAZ activation and explore the role of their downstream targets in driving tumor angiogenesis. We further discuss the potential for anti-cancer treatments and vascular normalization strategies to improve tumor therapies.

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Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.777018 ◽

2021 ◽

Vol 9 ◽

Author(s):

Wentao Tian ◽

Yi Liu ◽

Chenghui Cao ◽

Yue Zeng ◽

Yue Pan ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Patients ◽

Chronic Stress ◽

Epithelial Mesenchymal Transition ◽

Multi Drug Resistance ◽

Cancer Therapies ◽

Negative Effects ◽

Cancer Treatments ◽

Mesenchymal Transition ◽

Anti Cancer

Chronic stress is common among cancer patients due to the psychological, operative, or pharmaceutical stressors at the time of diagnosis or during the treatment of cancers. The continuous activations of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), as results of chronic stress, have been demonstrated to take part in several cancer-promoting processes, such as tumorigenesis, progression, metastasis, and multi-drug resistance, by altering the tumor microenvironment (TME). Stressed TME is generally characterized by the increased proportion of cancer-promoting cells and cytokines, the reduction and malfunction of immune-supportive cells and cytokines, augmented angiogenesis, enhanced epithelial-mesenchymal transition, and damaged extracellular matrix. For the negative effects that these alterations can cause in terms of the efficacies of anti-cancer treatments and prognosis of patients, supplementary pharmacological or psychotherapeutic strategies targeting HPA, SNS, or psychological stress may be effective in improving the prognosis of cancer patients. Here, we review the characteristics and mechanisms of TME alterations under chronic stress, their influences on anti-cancer therapies, and accessory interventions and therapies for stressed cancer patients.

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Regulation of signal transduction pathways in colorectal cancer: implications for therapeutic resistance

PeerJ ◽

10.7717/peerj.12338 ◽

2021 ◽

Vol 9 ◽

pp. e12338

Author(s):

Yeelon Yeoh ◽

Teck Yew Low ◽

Nadiah Abu ◽

Pey Yee Lee

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Abc Transporters ◽

Advanced Colorectal Cancer ◽

Drug Efflux ◽

Cancer Therapies ◽

Cancer Treatments ◽

Anti Cancer ◽

Notch Pathways ◽

Spectrum Of Patients

Resistance to anti-cancer treatments is a critical and widespread health issue that has brought serious impacts on lives, the economy and public policies. Mounting research has suggested that a selected spectrum of patients with advanced colorectal cancer (CRC) tend to respond poorly to both chemotherapeutic and targeted therapeutic regimens. Drug resistance in tumours can occur in an intrinsic or acquired manner, rendering cancer cells insensitive to the treatment of anti-cancer therapies. Multiple factors have been associated with drug resistance. The most well-established factors are the emergence of cancer stem cell-like properties and overexpression of ABC transporters that mediate drug efflux. Besides, there is emerging evidence that signalling pathways that modulate cell survival and drug metabolism play major roles in the maintenance of multidrug resistance in CRC. This article reviews drug resistance in CRC as a result of alterations in the MAPK, PI3K/PKB, Wnt/β-catenin and Notch pathways.

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NMN does not protect the ovarian reserve from cancer treatments

Reproduction ◽

10.1530/rep-19-0337 ◽

2020 ◽

Vol 159 (2) ◽

pp. 105-113 ◽

Cited By ~ 2

Author(s):

Jessica Stringer ◽

Ella Groenewegen ◽

Seng H Liew ◽

Karla Hutt

Keyword(s):

Ovarian Reserve ◽

Cancer Survival ◽

Survival Rates ◽

Primordial Follicle ◽

Cancer Therapies ◽

Γ Irradiation ◽

Cancer Treatments ◽

Primordial Follicles ◽

Nicotinamide Mononucleotide ◽

Cyclophosphamide Treatment

Primordial follicle oocytes are extremely vulnerable to DNA damage caused by exogenous agents, such as those commonly used to treat cancer. Consequently, female cancer patients often have diminished ovarian reserve, which if severe enough, can cause premature ovarian failure and early menopause. Advances in cancer therapies have resulted in significantly improved cancer survival rates; therefore, it is becoming increasingly important to devise strategies to protect the ovarian reserve from cancer treatments, to avoid loss of fertility and endocrine dysfunction. In this study, we aimed to determine whether supplementation with nicotinamide mononucleotide (NMN) could preserve the ovarian reserve following exposure to DNA-damaging cancer treatments. Adult female mice (n = 5–6/group) received saline or NMN (500 mg/kg/day) for 8 days. Mice were left untreated or exposed to γ-irradiation (0.1 Gy) or cyclophosphamide (150 mg/kg) on day 7 and ovaries and serum collected for analysis on day 12. We report that γ-irradiation treatment significantly reduced the number of primordial follicles, but supplementation with NMN did not prevent the observed follicle loss. Similarly, cyclophosphamide treatment significantly reduced primordial follicle numbers, but these losses were not prevented by NMN supplementation. In conclusion, depletion of the ovarian reserve following γ-irradiation or cyclophosphamide was not protected by NMN supplementation under the conditions employed in this study.

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Cardiac Toxicity of Cancer Chemotherapy

US Cardiology Review ◽

10.15420/usc.2017:2:2 ◽

2017 ◽

Vol 11 (1) ◽

pp. 20

Author(s):

Aarti Asnani ◽

Randall T Peterson ◽

◽

Keyword(s):

Antitumor Agents ◽

Cardiac Toxicity ◽

Survival Rates ◽

Clinical Manifestations ◽

Left Ventricular ◽

Cytotoxic Agents ◽

Cancer Therapies ◽

Cancer Treatments ◽

Number Of Patients ◽

Increased Risk

With the aging of the population, the number of patients diagnosed with cancer has grown significantly over the past few decades. In parallel, survival rates have improved due to the increased efficacy and tolerability of cancer treatments. As such, the acute and long-term toxicities of cancer therapies have become increasingly prominent as contributors to morbidity and mortality in cancer survivors. Cardiac toxicity can occur with a broad range of cancer treatments, from conventional cytotoxic agents to newer targeted and immune-based therapies. Common manifestations of chemotherapy-associated cardiotoxicity include asymptomatic left ventricular dysfunction, congestive heart failure, myocardial ischemia, myocarditis, QT prolongation, and arrhythmia. In this review, we will describe antitumor agents that have commonly been associated with an increased risk of cardiac toxicity, with an emphasis on clinical manifestations, underlying mechanisms, and cardioprotective strategies that can be implemented in this setting.

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Overview on Anticancer Drug Design and Development

Current Medicinal Chemistry ◽

10.2174/0929867325666171129215610 ◽

2018 ◽

Vol 25 (15) ◽

pp. 1704-1719 ◽

Cited By ~ 11

Author(s):

Sureyya Olgen

Keyword(s):

Kinase Inhibitors ◽

Molecular Design ◽

Resistance Mechanisms ◽

Cancer Drug ◽

Computational Techniques ◽

Cancer Therapies ◽

Cancer Drugs ◽

Design Strategies ◽

Advantages And Disadvantages ◽

Anti Cancer

Background: Many impediments of current anti-cancer therapies have urged scientists to discover new agents. As a result of growing spectrums of new targets and strategies and recent biological and biotechnological progresses, many anti-cancer agents such as monoclonal antibodies, small molecule tyrosine kinase inhibitors and epigenetic drugs have been reached to clinical trials. Objectives: This review helps to understand the rationale for the development of inhibitors against major targets such as cell growth, proliferation, survival, angiogenesis and recent targets such as proteasome, heat shock proteins, and epigenetics. Methods: Recent approaches of the target-based anti-cancer drug developments were highlighted to giving some examples from approved agents. Many factors, such as metabolic change, hypoxia, cancer precursors and cancer resistant cells, and their effect on drug resistance mechanisms were discussed. The impacts of advanced computational techniques to identify targets of cancer and designing more selective inhibitors were explained. Results: Contributions of recent techniques such as a network analysis, the precise modes of action and computational methodologies especially simulation of bio-molecular processes to clarify targets, mechanism actions and reasons of lack of efficacy of anti-cancer drugs have been explained. The relationship between the several mechanisms and molecular design strategies has been discussed. Conclusion: This review provides an overview of important targets and design strategies of anti-cancer drugs, advantages and disadvantages of these methods and evaluation of some currently used anticancer targets in clinical studies.

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