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  • A number of in vivo studies have investigated the antitumor

    2021-09-03

    A number of in vivo studies have investigated the antitumor activity of distinct GSK-3 inhibitors in a variety of cancer cell line-derived tumor xenograft models [14], [21], [22], [24], [33], [39], [40]. These studies utilized toolkit GSK-3 inhibitors as monotherapies. Although inhibition of tumor growth was reported, the antitumor effects were modest and the compounds used in these studies were not amenable for clinical development. In order to evaluate 9-ING-41 in combination with chemotherapy in vivo, we established two PDX models of metastatic breast cancer, BC-1 and BC-2, using metastatic pleural effusion pri-724 obtained from breast cancer patients who had failed multiple cycles of treatment in the clinic. PDX tumor models have emerged as a promising approach to evaluate the effects of cancer drugs on patient tumors and provide a new tool for evaluating new oncology drug candidates under development [41]. Comparison of tumors from patients and corresponding PDX tumors have demonstrated consistency in histological appearance, growth, mutations and gene expression patterns when PDX models are passaged in vivo[41], [42], [43]. This preservation of molecular and histological characteristics in PDX models suggests that PDX models may be superior to traditional cell line xenografts and better predictive of treatment response of novel anticancer drugs, a hypothesis that has gained strong support from a recently published high throughput drug evaluation study using PDX models [41]. Although we found that BC-1 and BC-2 PDX tumors express ER, surprisingly, these tumors grow without estradiol supplementation in immunodeficient mice. We found that both of these PDX tumors carry activating mutations in ESR1 which confer ligand-independent activity to ER and make them resistant to tamoxifen and fulvestrant treatment [30], [31]. These mechanistic insights are consistent with the clinical course and responses of the BC-1 and BC-2 patient donors. We found that treatment with the combination of CPT-11 and 9-ING-41, in contrast to either agent used alone, led to regression of established BC-1 tumors. These data are consistent with results of the in vitro studies showing that 9-ING-41 potentiates the antitumor effect of CPT-11 in breast cancer cells after short-term exposure. In contrast to CPT-11-resistant BC-1 PDX tumors, which were also resistant to 9-ING-41 monotherapy at the dose and schedule evaluated in vivo, we found that the growth of BC-2 PDX tumors was partially inhibited by either 9-ING-41 or CPT-11 monotherapy. Tumor regressions were only observed in the BC-1 and BC-2 PDX models when 9-ING-41 and CPT-11 were used in combination. Thus, our in vivo results provide a rationale for combining 9-ING-41 and CPT-11 as a novel therapeutic approach for the treatment of metastatic breast cancer as well as exploring additional combinations of 9-ING-41 with chemotherapy more extensively in metastatic breast cancer PDX tumor models as part of future pre-clinical development.
    Conflict of interest
    Acknowledgments This study was supported by a generous donation from the Baskes Family to the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and by Cancer Center Support Grant2 P30 CA060553-19 (APM, AU) to the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. We thank Jian-Jun Wei, Jeremy Mathews, Demirkan Gursel, Stephen Rohan, Bernice Frederick and Bella Shmaltsuyev (Pathology Core Facility, Robert H. Lurie Comprehensive Cancer Center, Northwestern University) and Gennadiy Bondarenko (Center for Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Evanston, IL) for providing us clinical samples of breast cancer and technical assistance. We express our gratitude to Jody Hirsh for editorial assistance.
    Introduction Glucocorticoids (GCs) are the most effective anti-inflammatory and immunosuppressive agents for the treatment of severe inflammatory diseases such as asthma and rheumatoid arthritis (Schäcke pri-724 et al., 2002). Several reports have shown that excess endogenous and exogenous GC exposure has been associated with the development of glucose deregulation such as glucose intolerance, insulin resistance (IR), hyperglycemia and eventually diabetes mellitus in both (Hoes et al., 2011; Di Dalmazi et al., 2012; Rafacho et al., 2014; Pasieka and Rafacho, 2016).