Eleven groups of fifty rats each were kept under uniform conditions of management and their life-spans under different treatments were compared. Females lived longer than males, while ovariectomy tended to shorten the life-span of females and castration to lengthen that of males. Implantation of gonadectomized rats with oestradiol benzoate did not prolong the life-span of the females but it did tend to prolong that ofmales. Implantation of gonadectomized rats with testosterone propionate tended to shorten the average life-span of both sexes. Unbred females outlived bred ones, on the average, but the difference was not significant at the 5% level. Late initial breeding appeared to be more harmful than breeding for the first time at the usual age for laboratory rats. Light breeding had little or no effect upon the average longevity of males. These conclusions are tentative. The results are consistent but they mostly lack acceptable statistical significance. The most significant result statistically was that rats exposed to their own or implanted oestrogens had a longer average life-span than did those exposed to their own or to implanted testosterone.

Endocrine-disrupting chemicals (EDCs)—including butyl benzyl phthalate (BBP), perfluorooctanoic acid (PFOA), and zeranol (α-ZAL, referred to as ZAL hereafter)—can interfere with the endocrine system and produce adverse effects. It remains unclear whether pubertal exposure to low doses of BBP, PFOA, and ZAL has an impact on breast development and tumorigenesis. We exposed female Sprague Dawley rats to BBP, PFOA, or ZAL through gavage for 21 days, starting on day 21, and analyzed their endocrine organs, serum hormones, mammary glands, and transcriptomic profiles of the mammary glands at days 50 and 100. We also conducted a tumorigenesis study for rats treated with PFOA and ZAL using a 7,12-dimethylbenz[a]anthracene (DMBA) model. Our results demonstrated that pubertal exposure to BBP, PFOA, and ZAL affected endocrine organs and serum hormones, and induced phenotypic and transcriptomic changes. The exposure to PFOA + ZAL induced the most phenotypic and transcriptomic changes in the mammary gland. PFOA + ZAL downregulated the expression of genes related to development at day 50, whereas it upregulated genes associated with tumorigenesis at day 100. PFOA + ZAL exposure also decreased rat mammary tumor latency, reduced the overall survival of rats after DMBA challenge, and affected the histopathology of mammary tumors. Therefore, our study suggests that exposure to low doses of EDCs during the pubertal period could induce changes in the endocrine system and mammary gland development in rats. The inhibition of mammary gland development by PFOA + ZAL might increase the risk of developing mammary tumors through activation of signaling pathways associated with tumorigenesis.

No abstract

The majority of gastrointestinal stromal tumors (GIST) harbor oncogenic mutations in the receptor tyrosine kinase KIT or platelet-derived growth factor receptor alpha (PDGFRA). Small molecule kinase inhibitors such as imatinib mesylate (IM) have significantly improved the clinical management of GIST by targeting these mutant receptors. Despite strong overall response rates to IM, disease progression generally occurs with time. Inhibiting targets other than, or in addition to, KIT/PDGFRA may provide additional therapeutic benefit in GIST patients. Both AKT and FGFR signaling have recently been reported to be resistance mechanisms associated with survival of IM-resistant GIST cell lines and tumors. In this study, we performed in vitro and in vivo experiments to assess the potential benefit of combining IM with the ArQule AKT inhibitors Miransertib (ARQ 092) and ARQ 751 and the FGFR inhibitor, Derazantinib (ARQ 087). To evaluate in vitro drug sensitivity, a panel of IM-sensitive (GIST-T1, GIST882) and resistant GIST cell lines (GIST-T1/829, GIST430) were subjected to drug treatment for 72 hours before measuring viability with the Cell Titer Blue Viability Assay. Synergy between IM and Miransertib, ARQ 751 and Derazantinib was quantified using the Chou-Talalay algorithm to calculate CI values. CI values <1 are considered synergistic. The 3:1 molar ratio of the three tested combinations demonstrated synergistic CI values in all four GIST lines. Immunoblot assays confirmed that drugs inhibited their intended targets in each cell line following six-hour drug treatment. Interestingly, a significant decrease in the activation of a downstream signaling protein, p-S6, was observed in the AKTi+ IM -treated cells compared to cells treated with single agents. In vivo studies evaluating Miransertib, ARQ 751 and Derazantinib as monotherapies and in combination with IM were performed using GIST-T1 and GIST430 xenograft models, as well, as an IM-resistant, KIT exon 9-mutated GIST PDX model. In both IM-resistant GIST models, all three monotherapies (Miransertib, ARQ 751, Derazantinib) significantly inhibited tumor growth as compared to IM alone. In addition, combination therapy, with both AKTi and FGFRi, provided significantly greater efficacy in both IM-sensitive and resistant xenograft models of GIST. Together, these studies demonstrate that IM in combination with the novel ArQule AKT inhibitors (Miransertib and ARQ 751) and FGFR inhibitor (Derazantinib) provide significantly improved efficacy compared to monotherapy in the tested models. These results provide justification for development of translational trials evaluating these combinations in GIST patients. Citation Format: Marya Kozinova, Shalina Joshi, Karthik Devarajan, Phillip Zook, Jimson W. D'Souza, Jeffrey M. Farma, Nestor Esnaola, Reza Foroughi, Yi Yu, Brian Schwartz, Terence Hall, Margaret von Mehren, Lori A. Rink. Combinations of imatinib mesylate with AKT inhibitor (miransertib, ARQ 751) or FGFR inhibitor (derazantinib) show synergy in GIST cell lines and preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4808.

The majority of gastrointestinal stromal tumor (GIST) patients develop resistance to the first-line KIT inhibitor, imatinib mesylate (IM), through acquisition of secondary mutations in KIT or bypass signaling pathway activation. In addition to KIT, AKT is a relevant target for inhibition, since the PI3K/AKT pathway is crucial for IM-resistant GIST survival. We evaluated the activity of a novel pan-AKT inhibitor, MK-4440 (formerly ARQ 751), as monotherapy and in combination with IM in GIST cell lines and preclinical models with varying IM sensitivities. Dual inhibition of KIT and AKT demonstrated synergistic effects in IM-sensitive and -resistant GIST cell lines. Proteomic analyses revealed upregulation of the tumor suppressor, PDCD4, in combination treated cells. Enhanced PDCD4 expression correlated to increased cell death. In vivo studies revealed superior efficacy of MK-4440/IM combination in an IM-sensitive preclinical model of GIST compared with either single agent. The combination demonstrated limited efficacy in two IM-resistant models, including a GIST patient-derived xenograft model possessing an exon 9 KIT mutation. These studies provide strong rationale for further use of AKT inhibition in combination with IM in primary GIST; however, alternative agents will need to be tested in combination with AKT inhibition in the resistant setting.