An Evolutionary Link between Cancer and Scleroderma: Somatic Cell Variation and Selection

Geneticists have recognized for some time that many genes exhibit pleiotropy, meaning that one mutation can manifest in two or more distinguishable phenotypic effects. In a fascinating study recently published in Science [2014 Jan 10;343(6167):152-7. doi:10.1126/science.1246886], Joseph et al. offer evidence for an example of pleiotropy in which the distinct phenotypic effects associated with mutation of the POLR3A gene, which encodes a subunit (RPC1) of RNA polymerase III, are associated with two different diseases: one or another form of cancer and an autoimmune disease (scleroderma). (more…)

The Case for Applying Negative Selection to Thoughts on Clonal Selection by Prospect Magazine’s Number One 2013 “World Thinker”

Currently, I am on vacation near the beach in South Carolina.  Consequently, I have opted for a topic that is bit different than the majority of my monthly commentaries in that it focuses not on a recent original report but instead on a conceptual point made in a book over thirty years ago.  Nevertheless, after a somewhat less strictly scientific diversion I will come to the central idea at issue, which is arguably the premier exemplar of the relevance of evolutionary principles to the operation of the immune system on short time scales, by which I refer to the concept of clonal selection.  But first, we make a foray into the world of magazine publishing and the niche within that domain focusing on the arguably more intellectual readers. (more…)

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…)

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…)

Immunoselective Subversion of Therapy for Myeloid Cancer

In a couple of previous posts I wrote about investigators who harnessed concepts derived from the study of evolution to generate therapeutic agents, in one case for a viral infection (2009a) and in another case for cancer (2009b). Below, I discuss a study from 2009 that illustrates how evolution of cellular populations can undermine treatment for acute myeloid leukemia or myelodysplastic syndrome, serious conditions affecting the hematopoietic system.

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