Citations

Abstract Background: Stage III triple negative(TN) inflammatory breast cancer(IBC) is associated with a poor prognosis evidenced by a 15 month(mo) median disease free survival(DFS) and overall survival(OS) of 34 mo. The substantial incidence of developing distant metastasis may be due to the prevalence of cancer cells with stem cell-like features (e.g. CD44+/CD24-) in TNIBC. The transcriptional pathway JAK2/STAT3 is associated with the survival of CD44+/CD24- cells, and preclinical data demonstrates overexpression of activated STAT3(pSTAT3) in > 95% of TNIBC. Preclinical studies have shown that ruxolitinib (Incyte®Corporation), an approved JAK1/JAK2 inhibitor, suppresses pSTAT3 in IBC patient derived xenograft models, and when combined with paclitaxel, results in a synergistic reduction in tumor weight. Given the lack of a known therapeutic target in TNIBC, this preoperative proof of principle study exploits the survival mechanism of CD44+/CD24- stem cells prevalent in this disease, by combining ruxolitinib(Rux) with paclitaxel(T) followed by doxorubicin/cyclophosphamide(AC). Methods: Up to 64 pts with newly diagnosed stage III TNIBC (cT4d, any N, M0) are eligible if they have adequate organ function and are willing to undergo 2 research biopsies(rbx) of the affected breast. Following baseline rbx, pts are randomized to a 7 day(d) run-in phase of Rux vs Rux(15 mg bid) + T(80mg/m2/wkx1). A 2nd rbx is obtained after the run-in phase. Pts randomized to RuxT continue to receive a total of Tx12 wks+Rux. Pts randomized to Rux alone, are re-randomized to receive Tx12 wks+Rux vs Tx12wks alone. Following T, all pts receive AC (A-60mg/m2,C-600mg/m2) every 14d x 4. Pts proceed to modified radical mastectomy (MRM) followed by chest wall/regional lymph nodes radiation therapy. Correlatives: To assess the effect of JAK inhibition with Rux on pSTAT3 and STAT3 related gene expression, molecular and genomic markers (e.g. RNA-seq, ChIPseq, FISH) will be determined in each rbx and residual tumor at MRM. The relative frequency and topology of CD44+/CD24- cell population and pSTAT3 expression by IHC will also be assessed in these tumor specimens. IL-6 and CRP plasma concentrations will be measured at baseline, prior to T and AC and prior to MRM. Statistics: The primary endpoint is change in markers of JAK/STAT inhibition. If the proportion of rbx exhibit a biologic response to Rux alone (i.e. change from pSTAT3 expression to pSTAT3 negative) is <10%, then Rux alone is minimally effective on JAK inhibition vs alternative hypothesis that Rux inhibits JAK if the proportion of biologic response is ≥33%. If ≥5/25 rbx treated with Rux alone have a biologic response then the hypothesis that biologic response is ≤10% is rejected with an error rate of 0.098 (target 0.10). If ≤4/25 rbx have a biologic response then the hypothesis that biologic response is ≥33% is rejected with an error rate of 0.05 (target 0.10). Biologic response of rbx with Rux alone will also be compared with the proportion of biologic response to RuxT (33% vs. 66% based upon presumed synergy with RuxT). Secondary endpoints are clinical: pathologic complete response in breast/lymph nodes, Residual Cancer Burden, DFS and OS. Clinical Trial Information: NCT02876302. Citation Format: Overmoyer B, Regan M, Polyak K, Brock J, Van Poznak C, King T, Haddad T, Stearns V, Hwang S, Winer E. TBCRC 039: Phase II study of combination ruxolitinib (INCB018424) with preoperative chemotherapy for triple negative inflammatory breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-01.

Abstract MUC1 is over expressed and aberrantly glycosolated in >60% of pancreatic ductal adenocarcinomas. Over expression of MUC1 in pancreatic cancer is known, however the functional role has yet to be fully elucidated due to a dearth of appropriate models. In the present study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1 null (KCKO) or express human MUC1 as a self antigen (KCM). We show that PDA mice lacking Muc1 have significantly slower tumor progression, with tumor weight reaching up to a third of the KCM tumor and half of KC tumor. One out of 10 KCKO mice developed secondary metastasis versus 6 out of 10 and 3 out of 10 KCM and KC respectively. Cell lines derived from KCKO tumors have significantly lower tumorigenic capacity compared to cells derived from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared to mice bearing the KCM tumors. In vitro, the KCKO cells have reduced proliferation and invasion compared to KCM cells and failed to respond to exogenous epidermal growth factor (EGF), platelet-derived growth factor (PDGF), or matrix metalloproteinase-9 (MMP9) stimuli. Further, significantly fewer KCKO cells entered the G2M phase of the cell cycle compared to the KCM cells, consequently more KCKO cells were observed at the S-phase of the cell cycle. Proteomics and western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of MAPK, as well as a significant decrease in Nestin and Tubulin α-2 chain expression in KCKO cells. Treatment of the KCM cells with a MEK1/2 inhibitor, U0126, completely abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, strongly suggesting that MUC1 is necessary for MAPK activity and downstream oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse in order to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1070. doi:10.1158/1538-7445.AM2011-1070

Abstract MUC1 is overexpressed and aberrantly glycosylated in more than 60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In this study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared with both KC and KCM. Cell lines derived from KCKO tumors have significantly less tumorigenic capacity compared with cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared with mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor, platelet-derived growth factor, or matrix metalloproteinase 9. Further, significantly less KCKO cells entered the G2–M phase of the cell cycle compared with the KCM cells. Proteomics and Western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of mitogen-activated protein kinase (MAPK), as well as a significant decrease in nestin and tubulin-α2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. Cancer Res; 71(13); 4432–42. ©2011 AACR.