The Focus of Selection, the Locus of Response, and Epigenetic Evasion

 

An interesting hypothesis in the evolutionary genetics of treating infections and cancers is that if the therapeutic agent does not directly target the pathogen or tumor, then the pathogen or tumor will be less likely to evolve resistance to that agent.  While early work on inhibitors of angiogenesis as potential cancer therapeutics suggested that such treatment did not elicit resistance by the tumor cells (Boehm et al., 1997), a recent study by Conley et al. (2012) raises doubts about the reliability of this notion in the context of antiangiogenic therapy for human breast cancer. (more…)

Evolutionary Variation as a ‘Lead Compound’

There is probably no more canonical example of the relevance of evolutionary genetics to clinical medicine than sickle cell disease.  The relevance of the sickle allele, in heterozygous form, at the beta-globin locus for resistance to falciparum malaria was published by Allison in 1954 (Lancet), and the precise amino acid substitution responsible for the phenotype of sickle cell disease, when the mutation is present in homozygous form, was identified by Ingram in 1956 (Nature).  Two recent papers (more…)

A Genomic Perspective on Pathogen Adaptation to Antibiotics and Vaccines

Among human pathogens, Streptococcus pneumoniae holds an especially prominent place in the history of biomedical investigation.  Griffith (1928) described the transforming principle, a soluble substance released by dead, virulent pneumococci that could render living avirulent pneumococci able to effectively kill a mouse.  Oswald Avery’s commitment to curing pneumococcal pneumonia (http://profiles.nlm.nih.gov/ps/retrieve/Narrative/CC/p-nid/37) led him and his collaborators to determine that the pneumococcal transforming principle was DNA (Avery et al., 1944).  It was also Avery’s and his collaborators’ work on pneumococci that provided some of the first insights into the chemical nature of most bacterial capsules. (more…)

Chemotherapy-Associated Evolution in Melanoma

Arguably, the most exciting trend of the last decade in chemotherapy for tumors based on traditional small molecule agents is the use of drugs that target specific protein kinases that participate in signaling pathways crucial for tumor growth (Solit and Sawyers, 2010).  The first example was imatinib (Druker et al., 2001) for the treatment of chronic myeloid leukemia (CML).  Subsequently imatinib was found to inhibit two tyrosine kinases (KIT and PGGFRA) that are crucial for a different cancer, gastrointestinal stromal tumor.   In CML, imatinib proved effective and relatively non-toxic but not curative (Solit and Sawyers, 2010).  One problematic aspect of therapy with imatinib was the development of tumor cell resistance (Shah et al., 2002).  Investigation of the genetic origin of resistance to imatinib revealed mutations in the target kinase, BCR-ABL (Shah et al., 2002).  This knowledge permitted development of second-generation inhibitiors (dasatinib and nilotinib) of the same kinase (Shah et al., 2004; Weisberg et al., 2005) that can be used in case of failed treatment with imatinib (Kantarjian et al., Blood 2010) and appear to have therapeutic advantages (over imatinib) including greater potency and reduced risk of eliciting resistance (Talpaz et al., 2006; Kantarjian et al., 2007; Kantarjian et al., NEJM 2010; Saglio et al., 2010).

In the case of the most lethal skin cancer (http://www.skincancer.org/Melanoma/), melanoma, the serine/threonine kinase, B-RAF, was shown to be mutated in greater than 60% of tumors.  The most common tumor-associated mutation (V600E; i.e., valine to glutamic acid at amino acid 600) was demonstrated to increase signaling through the downstream effectors MEK and ERK, consistent with a causal role for the V600E B-RAF mutation in melanoma (Davies et al., 2002).   As occurred with imatinib treatment of patients suffering from CML, however, treatment of melanoma patients with an inhibitor (PLX4032) of the mutated B-RAF led to tumor resistance. (more…)

Evolutionary Erosion of Anti-Microbial Magic

In the early years of the last century, Paul Ehrlich coined the term “magic bullet” to indicate a therapeutic agent that targeted an infectious agent or tumor with exquisite specificity (Schwartz, 2004).  He was inspired by his work with antibodies to imagine a future age of impressively discriminating and extremely effective drugs.  Perhaps the class of therapeutic agents with the longest and most impressive record of illustrating this concept has been antibiotics.  However, as a recent example (Kumarasamy et al., 2010) from the vast and continuously growing literature on antibiotic resistance illustrates, the ever-expanding list of evolving mechanisms through which bacteria counteract the actions of these therapeutic agents has put their continuing effectiveness in jeopardy. (more…)