Combining Evolution and Cancer therapy: A review of the Mathematical Approach

: Conventional cancer therapy kills tumors by applying the maximum tolerable dose of therapy. However, it leads to the development of tumoral heterogeneity and resistance, hence leading to therapy failure and progression. It is necessary to design therapies keeping in mind the evolutionary dynamics of tumors to minimize resistance and delay progression. Mathematical models are of great importance in oncology as they assist in the recreation of the tumor microenvironment, predict the outcomes of treatment strategies and elucidate fundamentals of tumor growth and resistance development. The body of literature covering models which incorporate evolutionary dynamics is vast. This paper provides an overview of existing models of “evolutionary therapy”, including ordinary differential equations, fitness, and probability functions.

Download Full-text

Evolutionary Dynamics of Treatment-Induced Resistance in Cancer Informs Understanding of Rapid Evolution in Natural Systems

Frontiers in Ecology and Evolution ◽

10.3389/fevo.2021.681121 ◽

2021 ◽

Vol 9 ◽

Author(s):

Mariyah Pressley ◽

Monica Salvioli ◽

David B. Lewis ◽

Christina L. Richards ◽

Joel S. Brown ◽

...

Keyword(s):

Cancer Cells ◽

Induced Resistance ◽

Evolutionary Dynamics ◽

Management Strategies ◽

Rapid Evolution ◽

Maximum Tolerable Dose ◽

Time To Progression ◽

Speed Of Evolution ◽

Adaptive Therapy ◽

Tolerable Dose

Rapid evolution is ubiquitous in nature. We briefly review some of this quite broadly, particularly in the context of response to anthropogenic disturbances. Nowhere is this more evident, replicated and accessible to study than in cancer. Curiously cancer has been late - relative to fisheries, antibiotic resistance, pest management and evolution in human dominated landscapes - in recognizing the need for evolutionarily informed management strategies. The speed of evolution matters. Here, we employ game-theoretic modeling to compare time to progression with continuous maximum tolerable dose to that of adaptive therapy where treatment is discontinued when the population of cancer cells gets below half of its initial size and re-administered when the cancer cells recover, forming cycles with and without treatment. We show that the success of adaptive therapy relative to continuous maximum tolerable dose therapy is much higher if the population of cancer cells is defined by two cell types (sensitive vs. resistant in a polymorphic population). Additionally, the relative increase in time to progression increases with the speed of evolution. These results hold with and without a cost of resistance in cancer cells. On the other hand, treatment-induced resistance can be modeled as a quantitative trait in a monomorphic population of cancer cells. In that case, when evolution is rapid, there is no advantage to adaptive therapy. Initial responses to therapy are blunted by the cancer cells evolving too quickly. Our study emphasizes how cancer provides a unique system for studying rapid evolutionary changes within tumor ecosystems in response to human interventions; and allows us to contrast and compare this system to other human managed or dominated systems in nature.

Download Full-text

Discovery of an Unexpected Similarity in Ligand Binding Between BRD4 and PPARγ

10.26434/chemrxiv.11472618.v1 ◽

2019 ◽

Author(s):

Lina Humbeck ◽

Jette Pretzel ◽

Saskia Spitzer ◽

Oliver Koch

Keyword(s):

Cancer Therapy ◽

Drug Targets ◽

Synergistic Effects ◽

Complex Structure ◽

Peroxisome Proliferator ◽

Resistance Development ◽

Peroxisome Proliferator Activated Receptor ◽

Starting Point ◽

Fundamental Research ◽

Important Drug

Knowledge about interrelationships between different proteins is crucial in fundamental research for the elucidation of protein networks and pathways. Furthermore, it is especially critical in chemical biology to identify further key regulators of a disease and to take advantage of polypharmacology effects. A comprehensive scaffold-based analysis uncovered an unexpected relationship between bromodomain-containing protein 4 (BRD4) and peroxisome-proliferator activated receptor gamma (PPARγ). They are both important drug targets for cancer therapy and many more important diseases. Both proteins share binding site similarities near a common hydrophobic subpocket which should allow the design of a polypharmacology-based ligand targeting both proteins. Such a dual-BRD4-PPARγ-modulator could show synergistic effects with a higher efficacy or delayed resistance development in, for example, cancer therapy. Thereon, a complex structure of sulfasalazine was obtained that involves two bromodomains and could be a potential starting point for the design of a bivalent BRD4 inhibitor.

Download Full-text

Cancer Fighting SiRNA-RRM2 Loaded Nanorobots

Pharmaceutical Nanotechnology ◽

10.2174/2211738508666200128120142 ◽

2020 ◽

Vol 8 (2) ◽

pp. 79-90

Author(s):

Arjun Sharma ◽

Pravir Kumar ◽

Rashmi K. Ambasta

Keyword(s):

Cancer Therapy ◽

Dna Synthesis ◽

Cancer Progression ◽

Sirna Delivery ◽

Predictive Marker ◽

The Body ◽

Tumor Site ◽

Target Delivery ◽

Target Effect

Background: Silencing of several genes is critical for cancer therapy. These genes may be apoptotic gene, cell proliferation gene, DNA synthesis gene, etc. The two subunits of Ribonucleotide Reductase (RR), RRM1 and RRM2, are critical for DNA synthesis. Hence, targeting the blockage of DNA synthesis at tumor site can be a smart mode of cancer therapy. Specific targeting of blockage of RRM2 is done effectively by SiRNA. The drawbacks of siRNA delivery in the body include the poor uptake by all kinds of cells, questionable stability under physiological condition, non-target effect and ability to trigger the immune response. These obstacles may be overcome by target delivery of siRNA at the tumor site. This review presents a holistic overview regarding the role of RRM2 in controlling cancer progression. The nanoparticles are more effective due to specific characteristics like cell membrane penetration capacity, less toxicity, etc. RRM2 have been found to be elevated in different types of cancer and identified as the prognostic and predictive marker of the disease. Reductase RRM1 and RRM2 regulate the protein and gene expression of E2F, which is critical for protein expression and progression of cell cycle and cancer. The knockdown of RRM2 leads to apoptosis via Bcl2 in cancer. Both Bcl2 and E2F are critical in the progression of cancer, hence a gene that can affect both in regulating DNA replication is essential for cancer therapy. Aim: The aim of the review is to identify the related gene whose silencing may inhibit cancer progression. Conclusion: In this review, we illuminate the critical link between RRM-E2F, RRM-Bcl2, RRM-HDAC for the therapy of cancer. Altogether, this review presents an overview of all types of SiRNA targeted for cancer therapy with special emphasis on RRM2 for controlling the tumor progression.

Download Full-text

Efficacy of a novel lantibiotic, CMB001, against MRSA

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkab040 ◽

2021 ◽

Author(s):

Jerzy Karczewski ◽

Christine M Brown ◽

Yukari Maezato ◽

Stephen P Krasucki ◽

Stephen J Streatfield

Keyword(s):

Antibacterial Activity ◽

Pharmacokinetic Analysis ◽

Maximum Tolerable Dose ◽

In Vivo Efficacy ◽

Clostridioides Difficile ◽

Alternative Treatment Option ◽

Significant Damage ◽

Tolerable Dose

Abstract Objectives To evaluate the efficacy of a novel lantibiotic, CMB001, against MRSA biofilms in vitro and in an in vivo experimental model of bacterial infection. Methods Antibacterial activity of CMB001 was measured in vitro after its exposure to whole blood or to platelet-poor plasma. In vitro efficacy of CMB001 against a Staphylococcus aureus biofilm was studied using scanning electron microscopy. The maximum tolerable dose in mice was determined and a preliminary pharmacokinetic analysis for CMB001 was performed in mice. In vivo efficacy was evaluated in a neutropenic mouse thigh model of infection. Results CMB001 maintained its antibacterial activity in the presence of blood or plasma for up to 24 h at 37°C. CMB001 efficiently killed S. aureus within the biofilm by causing significant damage to the bacterial cell wall. The maximum tolerable dose in mice was established to be 10 mg/kg and could be increased to 30 mg/kg in mice pretreated with antihistamines. In neutropenic mice infected with MRSA, treatment with CMB001 reduced the bacterial burden with an efficacy equivalent to that of vancomycin. Conclusions CMB001 offers potential as an alternative treatment option to combat MRSA. It will be of interest to evaluate the in vivo efficacy of CMB001 against infections caused by other pathogens, including Clostridioides difficile and Acinetobacter baumannii, and to expand its pharmacokinetic/pharmacodynamic parameters and safety profile.

Download Full-text

Clostridial Spores for Cancer Therapy: Targeting Solid Tumour Microenvironment

Journal of Toxicology ◽

10.1155/2012/862764 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Brittany Umer ◽

David Good ◽

Jozef Anné ◽

Wei Duan ◽

Ming Q. Wei

Keyword(s):

Cancer Therapy ◽

Solid Tumour ◽

Early Stage ◽

Treatment Options ◽

Anaerobic Bacteria ◽

Past Research ◽

Tumour Microenvironment ◽

The Body ◽

Solid Tumours ◽

Current Status

Solid tumour accounts for 90% of all cancers. The current treatment approach for most solid tumours is surgery, however it is limited to early stage tumours. Other treatment options such as chemotherapy and radiotherapy are non-selective, thus causing damage to both healthy and cancerous tissue. Past research has focused on understanding tumour cells themselves, and conventional wisdom has aimed at targeting these cells directly. Recent research has shifted towards understanding the tumour microenvironment and it’s differences from that of healthy cells/tissues in the body and then to exploit these differences for treatmeat of the tumour. One such approach is utilizing anaerobic bacteria. Several strains of bacteria have been shown to selectively colonize in solid tumours, making them valuable tools for selective tumour targeting and destruction. Amongst them, the anaerobicClostridiumhas shown great potential in penetration and colonization of the hypoxic and necrotic areas of the tumour microenvironment, causing significant oncolysis as well as enabling the delivery of therapeutics directly to the tumourin situ. Various strategies utilizingClostridiumare currently being investigated, and represent a novel area of emerging cancer therapy. This review provides an update review of tumour microenvironment as well as summary of the progresses and current status of Clostridial spore-based cancer therapies.

Download Full-text

Concepts in cardio-oncology: definitions, mechanisms, diagnosis and treatment strategies of cancer therapy-induced cardiotoxicity

Future Oncology ◽

10.2217/fon.15.349 ◽

2016 ◽

Vol 12 (6) ◽

pp. 855-870 ◽

Cited By ~ 12

Author(s):

Chanaka D Wickramasinghe ◽

Kim-Lien Nguyen ◽

Karol E Watson ◽

Gabriel Vorobiof ◽

Eric H Yang

Keyword(s):

Cancer Therapy ◽

Treatment Strategies ◽

Diagnosis And Treatment

Download Full-text

Three Acupoints of Acupressure Improve the Anxiety Level in Cancer Patients based on Types of Cancer Therapy

Indonesian Journal of Cancer ◽

10.33371/ijoc.v13i4.654 ◽

2019 ◽

Vol 13 (4) ◽

pp. 110

Author(s):

Yesiana Dwi Wahyu Werdani

Keyword(s):

Cancer Therapy ◽

Cancer Patients ◽

Anxiety Level ◽

The Body ◽

Rank Test ◽

P Value ◽

Chemotherapy Group ◽

Post Test ◽

Physical Disorders ◽

Signed Rank Test

Background: Cancer and its therapeutic management trigger the multiorgans physical disorders, that can cause the patient to worry and become anxious about the condition. Three acupoints of acupressure therapy stimulates relaxation of the body and can reduce anxiety. The purpose was to determine the influence of three acupoints of acupressure therapy to improve the anxiety level in cancer patients based on types of cancer therapy.Methods: This was an interventional study using pre-experiment pre-test post-test design. Samples were 30 cancer patients living at the Indonesian Cancer Foundation East Java Branch Surabaya Indonesia, taken by purposive technique sampling based on inclusion criteria. The instrument was Beck Anxiety Inventory that it was valid and reliable based on the test. Ethical feasibility tests has been carried out. Acupressure therapy is given on acupoint St36, Li4 and Li11. It conducted 2 times per week for 4 weeks. Wilcoxon Signed Rank Test was applied to analyze this result with p < 0.05.Results: There was a significant effect of acupressure for improving anxiety levels in both groups with p value in the chemotherapy group 0.001 and in the chemoradiotherapy group 0.002. But a greater influence occurred in the chemotherapy group compared to chemoradiotherapy group.Conclusions: Acupressure therapy in three acupoints can stimulate relaxation condition, it can decrease the anxiety level for cancer patients with all types of cancer therapy.

Download Full-text

Maximum Tolerable Dose (MTD)

Wiley Encyclopedia of Clinical Trials ◽

10.1002/9780471462422.eoct627 ◽

2008 ◽

Author(s):

Sylvie Chevret

Keyword(s):

Maximum Tolerable Dose ◽

Tolerable Dose

Download Full-text

Recent progress of nanomedicine-induced ferroptosis for cancer therapy

Biomaterials Science ◽

10.1039/d1bm00721a ◽

2021 ◽

Author(s):

Hajra Zafar ◽

Faisal Raza ◽

Siyu Ma ◽

Yawen Wei ◽

Jun Zhang ◽

...

Keyword(s):

Cancer Therapy ◽

Recent Progress ◽

Treatment Strategies ◽

Current Treatment ◽

High Efficacy ◽

Innovative Therapies

The current treatment strategies for cancer therapy have posed many problems in achieving high efficacy. Therefore, an urgent step is needed to develop innovative therapies that can win beyond satisfactory...

Download Full-text