The Meyerson lab recently discovered a small molecule compound, DNMDP (6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one) that selectively kills cancer cell llnes at nM potency (de Waal et al, 2016). Unlike typical targeted therapies that leverage dependencies in cancer cells created by genomic alterations, DNMDP induces cancer cell death by a gain-of-function mechanism involving the formation of a complex between phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12). To probe the mechanism of action of DNMDP, Xiaoyun et al. studied the genomic determinants of cancer cell response to DNMDP, finding a linear correlation between DNMDP sensitivity and PDE3A protein levels, and a requirement for expression of SLFN12 and the aryl hydrocarbon receptor-interacting protein, AIP. They further demonstrated that the PDE3A catalytic domain is necessary and sufficient for mediating sensitivity to DNMDP, and that PDE3B can substitute for PDE3A. In the absence of AIP, there is no PDE3A-SLFN12 complex formation and cells no longer respond to DNMDP-induced cancer cell killing. This study provides new insight into how DNMDP, through the PDE3A-SLFN12 complex, mediates cell death.
Andrew joined our team after undergraduate studies in biology at Worcester Polytechnic Institute. He has worked under the supervision of Xiaoyun Wu and Heidi Greulich, focused on the PDE3A-SLFN12 project. Andrew did structure function analyses on PDE3A-SLFN12 complex formation as well as analysis of the AIP protein required for complex formation. In the last few months, he and Elisa Aquilanti have done one of our few “permitted” experiments, an elegant study of the effect of a SLFN12 complex-forming compound on intracranially injected glioblastomas in mice.
Andrew has also contributed to lab life in lots of good ways, including serving as our safety officer at the Broad and being very positive and helpful to the team.
We thank Andrew and wish him good luck as he begins his PhD studies at Johns Hopkins!
Zhouwei and Netta studied synchronous primary ileal neuroendocrine tumors (NETs) to identify recurrent copy-number alterations. They confirmed that chromosome (chr) 18 loss of heterozygosity (LOH) is the most common copy-number alteration. Interestingly, they identified three different chr18 LOH patterns in different tumors from the same patients. These different chr18 LOH patterns suggest that synchronous primary ileal NETs are likely to develop independently, via a mechanism that is not currently understood.
During the lab shutdown, Matthew presented at the The DF/HCC Connect:Science seminar series on the relationship of the human microbiome and cancer. This seminar series aims to connect scientists around the world while social distancing. Watch Matthew’s talk here!