Evolutionary therapy is a subfield of evolutionary medicine that utilizes concepts from evolutionary biology in management of diseases caused by evolving entities such as cancer and microbial infections. [1] These evolving disease agents adapt to selective pressure introduced by treatment, allowing them to develop resistance to therapy, making it ineffective. [2]
Evolutionary therapy relies on the notion that Darwinian evolution is the main reason behind lethality of late stage cancer and multi-drug resistant bacterial infections such as methicillin-resistant Staphylococcus aureus. [3] Thus, evolutionary therapy suggests that treatment of such highly dynamic evolving diseases should be changing over time to account for changes in disease populations. [4] Adaptive treatment strategies typically cycle between different drugs or drug doses to take advantage of predictable patterns of disease evolution. This is in contrast to standardized treatment approach which is applied to all patients and equally based on their cancer type and grade. There are still numerous obstacles to the use of evolutionary therapy in clinical practice. These obstacles include high contingency of trajectory, speed of evolution, and inability to track the population state of disease over time. [5] [6]
Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. [7] All malignant cancers are fundamentally governed by Darwinian dynamics of the somatic evolution in cancer. Malignant cancers are dynamically evolving clades of cells living in distinct microhabitats that almost certainly ensure the emergence of therapy-resistant populations. Cytotoxic cancer therapies also impose intense evolutionary selection pressures on the surviving cells and thus increase the evolutionary rate. Importantly, the principles of Darwinian dynamics also embody fundamental principles that can illuminate strategies for the successful management of cancer. [8] [9] Eradicating the large, diverse and adaptive populations found in most cancers presents a formidable challenge. One centimetre cubed of cancer contains about 10^9 transformed cells and weighs about 1 gram, which means there are more cancer cells in 10 grams of tumour than there are people on Earth. Unequal cell division and differences in genetic lineages and microenvironmental selection pressures mean that the cells within a tumour are diverse both in genetic make-up and observable characteristics.
Resistance to one drug can lead to unwanted cross-resistance to some other drugs [10] and "collateral" sensitivity to yet other drugs [11] [12] [13] [14] [15] This phenomenon can be exploited to create cyclic therapeutic regimes where each subsequent drug would make population of evolving disease agent sensitive to at least one other drug, though this process is difficult secondary to the stochasticity of evolution. [5] Alternative methods include incorporating stochastic control algorithms to direct the evolution to specific states of resistance that encode sensitivity to other drugs. [16]
The standard approach to treating cancer is giving patients the maximum tolerated amount of chemotherapy with the goal of doing the maximum possible damage to the tumor without killing the patient. This method is relatively effective, but it also causes major toxicities. [17] Adaptive therapy is an evolutionary therapy that aims to maintain or reduce tumor volume by employing minimum effective drug doses or timed drug holidays. [18] [19] The timing and duration of these holidays, which relies on the ability to modulate resistant vs. sensitive populations of cancer cells through competition, is a subject which has been studied using dynamic programming [20] as well as optimal control [21] in theoretical studies based on Evolutionary game theory based models. The ability to modulate these populations secondary relies on the assumption that there is a both frequency-dependent selection, and an associated fitness cost to that resistance, a form of which, competitive exclusion, has been directly observed in EGFR lung cancer cell lines, [22] and posited in others.
Proof of principle for adaptive therapy has also been established in a recent phase 2 clinical trial [23] [24] as well as in vivo, [17] and more rigorous quantitative studies in vitro. [25]
In the evolutionary double bind, one drug causes increased susceptibility of the evolving cancer to another drug. Some have found that effectiveness might be based on interactions of populations through commensalism. [26] Others imply that population control may be possible if resistance to therapy requires a substantial and costly phenotypic adaptation that reduces the organism's fitness. [27]
Extinction therapy is inspired by mass extinction events from the Anthropocene era. [28] This treatment strategy is also sometimes referred to as first strike-second strike, where the first strike reduces the size and heterogeneity of a population so that the second strike that follows can kill the surviving, often fragmented population below a threshold by stochastic perturbations. [29]
A recent article. [30] introduced a potential therapeutic model that aims to create a tragedy of the commons within the populations of pathogens (bacteria, viruses, or even cancer). It is a well-established evolutionary prediction; cheaters can drive the whole population to go extinct. However, the success of free riders is usually supposed to be limited. Because cheater's patches will go extinct rapidly before they arrange successful migrations to other patches, this might be the fundamental problem of cheaters. However, this problem could be solved if we get a manipulated genetically engineered strain of the same pathogen, adopting a conditional defection strategy wherein free-riders would cooperate only for spread. The actors of this selfish strategy would have a high dispersal rate with the lowest possible cost because they share migration costs. Thus, the exploitation rate of public goods and interactions among defectors and cooperators will increase. In other words, this strain of conditional defectors can exclusively cooperate for all collective behaviors related to migration but defect otherwise. Therefore, these selfish successful migrators can be used as suicidal agents to drive the population of pathogens into the self-destruction process.
Although there is extensive modeling work on evolutionary therapy, [31] there are only a few completed and ongoing clinical trials that use evolutionary therapy. First one conducted in Moffitt Cancer Center on patients with metastatic castrate-resistant prostate cancer showed outcomes that "show significant improvement over published studies and a contemporaneous population." [32] This study met with some criticism. [33]
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of such infections. They may either kill or inhibit the growth of bacteria. A limited number of antibiotics also possess antiprotozoal activity. Antibiotics are not effective against viruses such as the ones which cause the common cold or influenza; drugs which inhibit growth of viruses are termed antiviral drugs or antivirals rather than antibiotics. They are also not effective against fungi; drugs which inhibit growth of fungi are called antifungal drugs.
Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between organisms other than by the ("vertical") transmission of DNA from parent to offspring (reproduction). HGT is an important factor in the evolution of many organisms. HGT is influencing scientific understanding of higher-order evolution while more significantly shifting perspectives on bacterial evolution.
Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, resistance has evolved. Antimicrobial resistance and antineoplastic resistance challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be multidrug-resistant.
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.
Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, but resistances to gefitinib can arise through other mutations. It is marketed by AstraZeneca and Teva.
Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a single disease, and often all the therapies are pharmaceutical. 'Pharmaceutical' combination therapy may be achieved by prescribing/administering separate drugs, or, where available, dosage forms that contain more than one active ingredient.
Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.
Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.
Cytochrome P450 17A1 is an enzyme of the hydroxylase type that in humans is encoded by the CYP17A1 gene on chromosome 10. It is ubiquitously expressed in many tissues and cell types, including the zona reticularis and zona fasciculata of the adrenal cortex as well as gonadal tissues. It has both 17α-hydroxylase and 17,20-lyase activities, and is a key enzyme in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens. More specifically, the enzyme acts upon pregnenolone and progesterone to add a hydroxyl (-OH) group at carbon 17 position (C17) of the steroid D ring, or acts upon 17α-hydroxyprogesterone and 17α-hydroxypregnenolone to split the side-chain off the steroid nucleus.
Cross-resistance is when something develops resistance to several substances that have a similar mechanism of action. For example, if a certain type of bacteria develops resistance to one antibiotic, that bacteria will also have resistance to several other antibiotics that target the same protein or use the same route to get into the bacterium. A real example of cross-resistance occurred for nalidixic acid and ciprofloxacin, which are both quinolone antibiotics. When bacteria developed resistance to ciprofloxacin, they also developed resistance to nalidixic acid because both drugs inhibit topoisomerase, a key enzyme in DNA replication. Due to cross-resistance, antimicrobial treatments like phage therapy can quickly lose their efficacy against bacteria. This makes cross-resistance an important consideration in designing evolutionary therapies.
Somatic evolution is the accumulation of mutations and epimutations in somatic cells during a lifetime, and the effects of those mutations and epimutations on the fitness of those cells. This evolutionary process has first been shown by the studies of Bert Vogelstein in colon cancer. Somatic evolution is important in the process of aging as well as the development of some diseases, including cancer.
A CDK inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance), a CDK4/6 inhibitor, in February 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. While there are multiple cyclin/CDK complexes regulating the cell cycle, CDK inhibitors targeting CDK4/6 have been the most successful, with 4 CDK4/6 inhibitors haven been FDA approved. No inhibitors targeting other CDKs have been FDA approved, but several compounds are in clinical trials.
Cellular noise is random variability in quantities arising in cellular biology. For example, cells which are genetically identical, even within the same tissue, are often observed to have different expression levels of proteins, different sizes and structures. These apparently random differences can have important biological and medical consequences.
Brigatinib, sold under the brand name Alunbrig among others, is a small-molecule targeted cancer therapy being developed by Ariad Pharmaceuticals, Inc. Brigatinib acts as both an anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.
Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.
Tumour heterogeneity describes the observation that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. This phenomenon occurs both between tumours and within tumours. A minimal level of intra-tumour heterogeneity is a simple consequence of the imperfection of DNA replication: whenever a cell divides, a few mutations are acquired—leading to a diverse population of cancer cells. The heterogeneity of cancer cells introduces significant challenges in designing effective treatment strategies. However, research into understanding and characterizing heterogeneity can allow for a better understanding of the causes and progression of disease. In turn, this has the potential to guide the creation of more refined treatment strategies that incorporate knowledge of heterogeneity to yield higher efficacy.
Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the bloodstream that is not associated with cells. ctDNA should not be confused with cell-free DNA (cfDNA), a broader term which describes DNA that is freely circulating in the bloodstream, but is not necessarily of tumor origin. Because ctDNA may reflect the entire tumor genome, it has gained traction for its potential clinical utility; "liquid biopsies" in the form of blood draws may be taken at various time points to monitor tumor progression throughout the treatment regimen.
Personalized onco-genomics (POG) is the field of oncology and genomics that is focused on using whole genome analysis to make personalized clinical treatment decisions. The program was devised at British Columbia's BC Cancer Agency and is currently being led by Marco Marra and Janessa Laskin. Genome instability has been identified as one of the underlying hallmarks of cancer. The genetic diversity of cancer cells promotes multiple other cancer hallmark functions that help them survive in their microenvironment and eventually metastasise. The pronounced genomic heterogeneity of tumours has led researchers to develop an approach that assesses each individual's cancer to identify targeted therapies that can halt cancer growth. Identification of these "drivers" and corresponding medications used to possibly halt these pathways are important in cancer treatment.
Cancer pharmacogenomics is the study of how variances in the genome influences an individual’s response to different cancer drug treatments. It is a subset of the broader field of pharmacogenomics, which is the area of study aimed at understanding how genetic variants influence drug efficacy and toxicity.
Multidrug-resistant bacteria are bacteria that are resistant to three or more classes of antimicrobial drugs. MDR bacteria have seen an increase in prevalence in recent years and pose serious risks to public health. MDR bacteria can be broken into 3 main categories: Gram-positive, Gram-negative, and other (acid-stain). These bacteria employ various adaptations to avoid or mitigate the damage done by antimicrobials. With increased access to modern medicine there has been a sharp increase in the amount of antibiotics consumed. Given the abundant use of antibiotics there has been a considerable increase in the evolution of antimicrobial resistance factors, now outpacing the development of new antibiotics.