Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies.

The greater efficacy of DNA-damaging drugs for pancreatic adenocarcinoma (PDAC) relies on targeting cancer-specific vulnerabilities while sparing normal organs and tissues due to their inherent toxicities. We tested LP-184, a novel acylfulvene analog, for its activity in preclinical models of PDAC carrying mutations in the DNA damage repair (DDR) pathways. Cytotoxicity of LP-184 is solely dependent on prostaglandin reductase 1 (PTGR1), so that PTGR1 expression robustly correlates with LP-184 cytotoxicity in vitro and in vivo. Low-passage patient-derived PDAC xenografts with DDR deficiencies treated ex vivo are more sensitive to LP-184 compared with DDR-proficient tumors. Additional in vivo testing of PDAC xenografts for their sensitivity to LP-184 demonstrates marked tumor growth inhibition in models harboring pathogenic mutations in ATR, BRCA1, and BRCA2. Depletion of PTGR1, however, completely abrogates the antitumor effect of LP-184. Testing combinatorial strategies for LP-184 aimed at deregulation of nucleotide excision repair proteins ERCC3 and ERCC4 established synergy. Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184.

Feasibility of intrafraction whole-body motion tracking for total marrow irradiation.

With image-guided tomotherapy, highly targeted total marrow irradiation (TMI) has become a feasible alternative to conventional total body irradiation. The uncertainties in patient localization and intrafraction motion of the whole body during hour-long TMI treatment may pose a risk to the safety and accuracy of targeted radiation treatment. The feasibility of near-infrared markers and optical tracking system (OTS) is accessed along with a megavoltage scanning system of tomotherapy. Three near-infrared markers placed on the face of a rando phantom are used to evaluate the capability of OTS in measuring changes in the markers' positions as the rando is moved in the translational direction. The OTS is also employed to determine breathing motion related changes in the position of 16 markers placed on the chest surface of human volunteers. The maximum uncertainty in locating marker position with the OTS is 1.5 mm. In the case of normal and deep breathing motion, the maximum marker position change is observed in anterior-posterior direction with the respective values of 4 and 12 mm. The OTS is able to measure surface changes due to breathing motion. The OTS may be optimized to monitor whole body motion during TMI to increase the accuracy of treatment delivery and reduce the radiation dose to the lungs.