Abstract
A better understanding of mechanistic insights into genes and enzymes implicated in rare diseases provide a unique opportunity for orphan drug development. Advances made in identification of synthetic lethal relationships between rare disorder genes with oncogenes and tumor suppressor genes have brought in new anticancer therapeutic opportunities. Additionally, the rapid development of small molecule inhibitors against enzymes that participate in DNA damage response and repair has been a successful strategy for targeted cancer therapeutics. Here, we discuss the recent advances in our understanding of how many rare disease genes participate in promoting genome stability. We also summarize the latest developments in exploiting rare diseases to uncover new biological mechanisms and identify new synthetic lethal interactions for anticancer drug discovery that are in various stages of preclinical and clinical studies.
Highlights
Rare diseases are defined as disorders that affect fewer than 200,000 people in the United States [1]. these disorders can often be chronic, debilitating, and life-limiting illnesses there are few effective therapies for these diseases (Figure 1) [1]
Most significantly in that it uses shorter homology overhangs (5–25 base pair) on the ends of the double-strand breaks during the alignment of the broken ends before religating them [15]. Though both these pathways are highly conserved throughout evolution, Homologous recombination (HR) appears to be the predominant mechanism of DSBR during embryogenesis, whereas Non-homologous end-joining (NHEJ) is a major pathway for repair in post-natal life and in the G0/G1 phase of the cell cycle [16]
Identifying target genes/enzymes, and understanding the mechanism(s) underlying the progression of rare cancers provides us with the opportunity to: (A) exploit the disease-causing gene as a therapeutic target, and (B) expand the repertoire of targets for orphan drug discovery and development
Summary
Rare diseases are defined as disorders that affect fewer than 200,000 people in the United States [1]. A second NHEJ concomitant pathway often referred to as alternative-NHEJ (Alt-NHEJ)/Microhomology-mediated end-joining (MMEJ) differs from NHEJ most significantly in that it uses shorter homology overhangs (5–25 base pair (bp)) on the ends of the double-strand breaks during the alignment of the broken ends before religating them [15]. Though both these pathways are highly conserved throughout evolution, HR appears to be the predominant mechanism of DSBR during embryogenesis (and S/G2 phases of cell cycle), whereas NHEJ is a major pathway for repair in post-natal life and in the G0/G1 phase of the cell cycle [16]. We discuss four DNA repair genes/gene networks: Werner helicase, Bloom helicase, ATM kinase and Fanconi Anemia proteins and how pharmacologically inhibiting these gene products in combination with a cancer driver mutation is synthetically lethal and can be exploited for developing orphan drugs
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