Andrew C. Bell

Proton Radiotherapy for Recurrent or Metastatic Head and Neck Cancers with Palliative Quad Shot

Purpose Some patients with previously treated, unresectable, recurrent or metastatic head and neck malignancies are not amenable to curative-intent treatment. Here, we investigated the quad-shot (RTOG 8502) regimen of hypofractionated proton radiotherapy (RT) in that patient population. Materials and Methods From 2013 to 2015, 26 patients with recurrent or metastatic cancers were treated with palliative proton RT to the head and neck with quad shot (3.7 Gy twice daily for 2 days). Patient characteristics and survival data were reviewed. Results Seventeen (65%) patients received ≥ 3 quad-shot cycles and 23 (88%) had prior head and neck RT. Overall palliative response was 73% (n = 19). The most common presenting symptom was pain (50%; n = 13), which improved in 85% (n = 22) of all patients. The overall grade-1 acute-toxicity rate was 58% (n = 15), and no acute grade 3 to 5 toxicities were observed. Conclusions The proton quad-shot regimen demonstrates favorable palliative response and toxicity profile, even in patients that received prior RT.

Inhibition of non-homologous end joining in Fanconi Anemia cells results in rescue of survival after interstrand crosslinks but sensitization to replication associated double-strand breaks

When Fanconi Anemia (FA) proteins were depleted in human U2OS cells with integrated DNA repair reporters, we observed decreases in homologous recombination (HR), decreases in mutagenic non-homologous end joining (m-NHEJ) and increases in canonical NHEJ, which was independently confirmed by measuring V(D)J recombination. Furthermore, depletion of FA proteins resulted in reduced HR protein foci and increased NHEJ protein recruitment to replication-associated DSBs, consistent with our observation that the use of canonical NHEJ increases after depletion of FA proteins in cycling cells. FA-depleted cells and FA-mutant cells were exquisitely sensitive to a DNA-PKcs inhibitor (DNA-PKi) after sustaining replication-associated double strand breaks (DSBs). By contrast, after DNA interstrand crosslinks, DNA-PKi resulted in increased survival in FA-deficient cells, implying that NHEJ is contributing to lethality after crosslink repair. Our results suggest FA proteins inhibit NHEJ, since repair intermediates from crosslinks are rendered lethal by NHEJ. The implication is that bone marrow failure in FA could be triggered by naturally occurring DNA crosslinks, and DNA-PK inhibitors would be protective. Since some sporadic cancers have been shown to have deficiencies in the FA-pathway, these tumors should be vulnerable to NHEJ inhibitors with replication stress, but not with crosslinking agents, which could be tested in future clinical trials.

Talazoparib is a Potent Radiosensitizer in Small Cell Lung Cancer Cell Lines and Xenografts

Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with a critical need for novel therapies. Our goal was to determine whether PARP inhibition could sensitize SCLC cells to ionizing radiation (IR) and if so, to determine the contribution of PARP trapping to radiosensitization. Experimental Design: Short-term viability assays and clonogenic survival assays (CSA) were used to assess radiosensitization in 6 SCLC cell lines. Doses of veliparib and talazoparib with equivalent enzymatic inhibitory activity but differing PARP trapping activity were identified and compared in CSAs. Talazoparib, IR, and their combination were tested in three patient-derived xenograft (PDX) models. Results: Talazoparib radiosensitized 5 of 6 SCLC cell lines in short-term viability assays and confirmed in 3 of 3 cell lines by CSAs. Concentrations of 200 nmol/L talazoparib and 1,600 nmol/L veliparib similarly inhibited PAR polymerization; however, talazoparib exhibited greater PARP trapping activity that was associated with superior radiosensitization. This observation further correlated with an increased number of double-stranded DNA breaks induced by talazoparib as compared with veliparib. Finally, a dose of 0.2 mg/kg talazoparib in vivo caused tumor growth inhibition in combination with IR but not as a single agent in 3 SCLC PDX models. Conclusions: PARP inhibition effectively sensitizes SCLC cell lines and PDXs to IR, and PARP trapping activity enhances this effect. PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of radiotherapy in SCLC. Clin Cancer Res; 24(20); 5143–52. ©2018 AACR.

MP98-04 DEFECTIVE ERCC2 CONFERS INCREASED CISPLATIN AND IONIZING RADIATION SENSITIVITY IN BLADDER CANCER CELLS

compared to those in AD conditions. Furthermore, T-DM1 significantly inhibited colony formation in soft agar compared to control IgG or trastuzumab. Since anoikis is a pre-requisite for metastasis, these results suggest that HER2 expression contributes to the establishment of metastasis and T-DM1 could have anti-metastatic potential. The bladder cancer cell line with the highest HER2 expression (BOY) was equivocal HER2 amplification by FISH (HER2/CEP17 ratio: 1.8, HER2 copy number: 4.7), which is known to correspond to HER2 IHC score 2+ in patient tissue. BOY responded most sensitively to T-DM1, and low concentration (10nM) T-DM1 induced apoptosis only in BOY. This suggests T-DM1 could be effective in patients with HER2 overexpression (IHC score 2+/3+). CONCLUSIONS: Our pre-clinical results suggest that T-DM1 could have anti-metastatic potential and be a promising targeted therapy for patients with HER2 score 2+/3+ UCB. T-DM1 warrants clinical evaluation in these patients.