bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P6-18-30: Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC)
Authors: Wang R , Singh J , Sterlin V , Goldstein M , Lake D , Wong S , Baselga J , Norton L , Dang C
Published: May 2019

Background: Neratinib (N) is a potent irreversible inhibitor of HER1, HER2, and HER4 and has been shown to have antitumor activity in patients (pts) with human epidermal growth factor receptor 2 (HER2) - positive breast cancer. A previous study of combination of neratinib with capecitabine (X) was associated with > G 3 diarrhea in > 20% of patients. Currently, the NALA study is evaluating this combination of N with X at standard schedule against control. X at 7 day on and 7 day off schedule (7/7) has been shown to be well-tolerated with less ≥G3 toxicities. We are conducting a phase Ib/II study of N with X (7/7) in pts with pretreated HER2+ MBC (NCT03377387). Methods: Eligible pts had HER2+ MBC, normal left ventricular ejection fraction (LVEF ≥ 50%); pts can have any and up to 4 prior chemotherapy-based treatments in phase Ib and II portions, respectively. Primary endpoints are to define maximum tolerated dose and efficacy in phase I and phase II portions, respectively. Secondary endpoints include safety and tolerability; exploratory endpoint is to quantify cell-free DNA to correlate with response for phase II portion. There were 4 cohorts for phase Ib with dose level 1 with starting dose of X at 1500 mg BID at 7/7 schedule with N at 240 mg daily. Results: As of July 1, 2018 8 pts have been enrolled in 2 cohorts. The median age is 63y (range: 57-79), and median ECOG is 0 (range: 0-1). 4 patients were treated at dose level 1 and 2 of 4 patients experienced dose-limiting toxicity with G3 diarrhea during cycle 1. Other significant toxicities included G3 hand foot syndrome (n=1), G3 fatigue (n=1) and G3 nausea (n=1). Three pts have now been treated at dose level -1 (X at 1000 mg twice daily 7/7 and N at 240 mg daily) and no ≥ G3 toxicities has been noted. Once MTD is reached, the phase II portion will occur to assess the efficacy and to further establish the safety and tolerability of capecitabine and neratinib at the MTD. Conclusions: The phase Ib/II study combining neratinib and capecitabine 7/7 is ongoing and updated result will be presented.

Citation Format: Wang R, Singh J, Sterlin V, Goldstein M, Lake D, Wong S, Baselga J, Norton L, Dang C. Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-30.
Abstract P6-20-10: Role of GPR110 in breast cancer
Authors: Bhat R , Qin L , De Angelis C , Sahay D , Bhargava D , Creighton C , Yadav P , Yazdanfard S , Alrawi A , Yadav V , Vasaikar S , Nanda S , Sethunath V , Fu X , Zhang B , Narkar V , Schiff R , Trivedi M
Published: May 2019

Our long-term goal is to discover adhesion GPCR targets in breast cancer. Our previous studies have found GPR110 to be overexpressed in tumorigenic cell population as well as in anti-HER2 drug-resistant derivatives of HER2+ breast cancer cells. In subsequent studies, we found that GPR110 knockdown inhibited anchorage-independent cell growth, mammosphere formation, and invasion/migration of HER2+ breast cancer cells. Conversely, overexpression of GPR110 by lentiviral delivery of cDNA enhanced anchorage-independent cell growth, mammosphere formation, and invasion/migration in HER2+ breast cancer cells. In addition, GPR110 overexpression led to increase in the % of Aldefluor-positive tumorigenic cell population, further emphasizing the role of GPR110 as a mediator of tumorigenesis in addition to the metastatic processes in HER2+ breast cancer. Among various subtypes of breast cancer, GPR110 expression was higher in HER2+ and basal subtypes, most of which are triple-negative (negative for ER, PR, and HER2), compared to luminal A and B subtypes. GPR110 was either gene amplified or upregulated in 4% of all breast cancers based on the publicly available TCGA dataset. GPR110 overexpression predicted poorer recurrence-free survival in triple-negative breast cancer. Furthermore, GPR110 was overexpressed in brain metastatic lesions compared to mammary tumors in patient-derived xenograft models of triple-negative breast cancer (WHIM2 and WHIM30). Knocking down GPR110 reduced anchorage-dependent and -independent cell growth, mammosphere formation, and invasion/migration of triple-negative breast cancer cells. Overall, our results suggest that GPR110 may be a potential drug target in HER2+ and triple-negative breast cancer. Drug discovery efforts to identify GPR110 antagonists will provide useful pharmacological tools for validating GPR110 as a drug target in breast cancer. Since GPR110 is also overexpressed in various other types of cancer, understanding the mechanism of GPR110 upregulation and signaling in cancer is an important future direction.

This work was supported by the Department of Defense Grants W81XWH-14-1-0340 and W81XWH-14-1-0341 to Drs. Trivedi and Schiff, respectively.

Citation Format: Bhat R, Qin L, De Angelis C, Sahay D, Bhargava D, Creighton C, Yadav P, Yazdanfard S, Alrawi A, Yadav V, Vasaikar S, Nanda S, Sethunath V, Fu X, Zhang B, Narkar V, Schiff R, Trivedi M. Role of GPR110 in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-10.
Abstract P6-20-12: FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells
Authors: Zhao M , Zhuo M-L , Zheng X , Su X , Meric-Bernstam F
Published: May 2019

Background:Abnormal FGFR1 alternative splicing is correlated with tumorigenicity and poor prognosis in several tumor types. We sought to determine the roles of FGFR1α and FGFR1β variants in breast cancer. Methods: TCGA breast cancer samples and cell lines were analyzed for FGFR1α and FGFR1β expression. MCF-10A cells were used to overexpress these variants. Cell growth was assessed by SRB and colony formation assays. Cell transformation was assessed by 3D-Matrigel, soft agar, cell motility assays. Cell survival assay was used to determine drug IC50. Results: In the TCGA, compared to FGFR1 non-amplified samples, FGFR1-amplified samples had significantly higher FGFR1α, but not FGR1β levels. FGFR1β expression levels and FGFR1β/FGFR1α ratio were higher in basal subtype samples than in luminal samples in both the TCGA and in a panel of breast cancer cell lines. Both FGFR1α and FGFR1b induced transformation of MCF-10A cells. However, only FGFR1β-expressing cells, not FGFR1α, enhanced cell growth, cell motility, and FGFR signaling. Cells with higher FGFR1β levels and FGFR1β/FGFR1α ratio were more sensitive to FGFR inhibitor BGJ-398. Interestingly, in ER-negative cells, BGJ-398 decreased FGFR1β levels, likely by increasing expression of splicing repressor PTBP1. In ER-positive cells, estrogen treatment increased FGFR1β levels by decreasing PTBP1 expression, which was blocked by 4-OHT. Lastly, combination treatment with BGJ-398 and 4-OHT synergistically inhibited cell survival. Conclusions: These findings suggest that FGFR1 alternative splicing plays an important role in breast cancer, where FGFR1β functions as a driver isoform. Further work is needed to assess FGFR1β prognostic and predictive role.

Citation Format: Zhao M, Zhuo M-L, Zheng X, Su X, Meric-Bernstam F. FGFR1β is a driver isoform of FGFR1 alternative splicing in breast cancer cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-12.
Abstract PD1-07: Withdrawn
Authors: Howell SJ , Waters S , Twelves C , Joffe J , Moon S , Bale C , Venkitaraman R , Bezecny P , Casbard A , Wilhelm-Benartzi C , Carucci M , Butler R , Alchami F , Jones R
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Howell SJ, Waters S, Twelves C, Joffe J, Moon S, Bale C, Venkitaraman R, Bezecny P, Casbard A, Wilhelm-Benartzi C, Carucci M, Butler R, Alchami F, Jones R. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-07.
Abstract PD4-02: Withdrawn
Authors: Wong MJ , Patel R , DeMartini WB , Todderud JE , Okamoto S , Ikeda DM
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Wong MJ, Patel R, DeMartini WB, Todderud JE, Okamoto S, Ikeda DM. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-02.
Abstract PD4-06: A clinical model for assessing the individual breast cancer risk in mammography screening
Authors: Eriksson M , Czene K , Pawitan Y , Hall P
Published: May 2019

Background. Mammography screening reduces breast cancer mortality, but is suboptimal for the breast cancers that are not detected by the screening. These women are identified as symptomatic interval cancers with more aggressive tumors and worse pronosis. To efficiently screen for breast cancer the individual breast cancer risk should be determined. We describe a model that is suited for bi-annual screening programs and estimates the 2-year risk of breast cancer. The risk model could be used at most mammography screening units without adding substantial cost.

Methods. The study was based on the population based prospective KARMA cohort including 70,877 participants. Mammograms were collected up to five years following baseline mammogram. A prediction model was developed using mammographic features (density, microcalcifications and masses), use of hormone replacement therapy (HRT), family history of breast cancer, menopausal status, and body mass index. Relative risks were calculated using conditional logistic regression and 2-year absolute risks were calculated

Results. Comparing women at highest and lowest mammographic density yielded a 5-fold higher risk of breast cancer for women at highest density. When adding microcalcifications and masses to the model, high-risk women had a nearly 9-fold higher risk of breast cancer compared to those at lowest risk. In the full model, taking HRT use, family history of breast cancer and menopausal status into consideration, area under the curve (AUC) reached 0.73.

We calculated the absolute 2-year risk of breast cancer based on national incidence and mortality rates. We also stratified women into risk groups using the NICE guidelines adapted to 2-year risks. The 20% women with moderate or high breast cancer risk were 7.6 times more likely to develop breast cancer compared to the general risk. Also 18% of the women showed 4 times reduced risk compared to the average population.

Conclusions. This risk model can improve mammography screening by identifying women that are in need of additional examination procedures. There is also a substantial proportion of women with low breast cancer risk who will have little benefit from screening.

Citation Format: Eriksson M, Czene K, Pawitan Y, Hall P. A clinical model for assessing the individual breast cancer risk in mammography screening [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-06.
Abstract PD4-08: Relationship between FDG-uptake and expression level of PD-L1 in primary ER positive/HER2 negative breast cancer
Authors: Hirakata T , Fijii T , Kaira K , Kurozumi S , Katayama A , Yajima R , Obayashi S , NaKazawa Y , Tokuda S , Yanai K , Shirabe K
Published: May 2019

Background: 18F-Fluorodeoxyglucose-positron emission tomography (FDG-PET) is used to evaluate the glucose metabolic rates of cancers. Several studies have reported that high FDG uptake is predictive of poor prognosis and aggressive features in patients with breast cancer (BC). FDG-uptake is influenced by many factors including inflammation. In this study, we investigated the relationship between FDG uptake and immunological factors, including degrees of stromal tumor-infiltrating lymphocytes (TILs), CD8 and programmed cell death ligand 1 (PD-L1) in ER positive/HER2 negative (ER+/HER2-) BC. No published study, to our knowledge, has assessed the association between FDG uptake and PD-L1 in BC cases, even though both represent prognosis. Methods: Invasive carcinoma tissues of 79 ER+/HER2- BC patients who underwent surgery without preoperative therapy were examined. PD-L1, CD8 and TILs expression were evaluated by immunohistochemically (IHC) method. The evaluation of PET was determined by standardized uptake value max (SUVmax). Multivariate linear regression analysis, including expression of PD-L1, CD8 and TILs, was performed to identify independent variable correlation with SUVmax. Results: Among the 79 ER+/HER2- BC (T1-4, N0-2, M0) patients, the analysis revealed that PD-L1 (P=0.005), lymphovascular invasion (P=0.011), large tumor size (p=0.001), lymph node meatstasis (P=0.010), and high nuclear grade (P=0.011) and premenopasal status (P=0.014) were significantly associated with high SUVmax in the primary tumor. To define predictive value for the expression of PD-L1, SUVmax cut offwas determined using receiver operating characteristic (ROC) analysis; low (<3.0) and high (≥3.0). Among the 30 cases with high SUVmax, 10 cases (33.3%) had PD-L1 positive expression in the primary tumor, while only 2 (4.1%) of the 49 cases with low SUVmax had PD-L1 positive expression in the primary tumor. Conclusions: The present study demonstrated that the finding of preoperative FDG uptake is associated with the expression of PD-L1 in ER+/HER2- BC. In light of our results, FDG uptake may be predictive of the expression of PD-L1 and may be reflective of immunological features as well as prognostic features among patients with ER+/HER2- BC.

Citation Format: Hirakata T, Fijii T, Kaira K, Kurozumi S, Katayama A, Yajima R, Obayashi S, NaKazawa Y, Tokuda S, Yanai K, Shirabe K. Relationship between FDG-uptake and expression level of PD-L1 in primary ER positive/HER2 negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-08.
Abstract PD6-05: Withdrawn
Authors: Kehm RD , Phillips K-A , Daly MB , Andrulis IL , Liao Y , Ma X , Zeinomar N , MacInnis RJ , Dite GS , John EM , Buys SS , Milne RL , Hopper JL , Terry MB
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Kehm RD, Phillips K-A, Daly MB, Andrulis IL, Liao Y, Ma X, Zeinomar N, MacInnis RJ, Dite GS, John EM, Buys SS, Milne RL, Hopper JL, Terry MB. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD6-05.
Abstract TS2-2: Clinical development of inhibitors of the PI3K pathway
Authors: Saura Manich C
Published: May 2019

The activation of the PI3K-AKT-mTOR pathway as a mechanism of resistance to different breast cancer treatments has been well described for years at the preclinical level. This observation, together with the high frequency of alterations of this pathway in patients with breast tumors (especially in the luminal subtype such as PI3KCA mutations, loss of PTEN function or AKT mutations) makes this pathway a highly desirable in inhibiting the growth of these tumor types.

The first clinical evidence that inhibition of the PI3K-AKT-mTOR pathway leads to increased progression-free survival in metastatic breast cancer came from the BOLERO-2 trial with the mTORC1-targeting agent everolimus, the only PI3K-AKT-mTOR pathway inhibitor approved to date in breast cancer. Potentially better drugs have subsequently been developed and tested. PI3K inhibitors were designed to potentiate the inhibition of the pathway to optimize treatment efficacy and improve the toxicity profile.

The first to be developed were the pan-PI3K inhibitors buparlisib and pictilisib. Results from pivotal clinical studies combining fulvestrant demonstrated increased efficacy but at the cost of increased toxicity that was considered clinically unacceptable. None of them consequently eceived approval for breast cancer treatment. It was hoped that Isoform-specific PI3K inhibitors (alpha or beta-sparing) would improve the toxicity profile and increase efficacy, especially in patients with molecular alterations in the PI3K-AKT-mTOR pathway. We are now witnessing interesting times for these drugs since we have seen the results of the two phase III studies with specific pathway inhibitors, taselisib and alpelisib. During this session we will carefully review the results of both studies in terms of efficacy and toxicity profile as well as those from other phase I-II clinical trials with these and other agents.

Representing the main challenges in the future, we still have to determine the best strategy to select those patients who will likely derive greater benefit from these therapies as well as establish the context in which they are most effective, taking into account the mechanisms of resistance that PI3K inhibitors can overcome or those that emerge during treatment with these drugs.

Citation Format: Saura Manich C. Clinical development of inhibitors of the PI3K pathway [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr TS2-2.
Abstract A05: Targeting the EMT-immunosuppression loop in lung cancer as a strategy to prevent metastasis
Authors: Chen Limo , Lou Yanyan , Heymach John , Wistuba Ignacio , Ullrich Stephen , Qin Xiao-Feng , Gibbons Don
Published: May 2019

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR01) of the Conference Proceedings.

Citation Format: Limo Chen, Yanyan Lou, John Heymach, Ignacio Wistuba, Stephen Ullrich, Xiao-Feng Qin, Don Gibbons. Targeting the EMT-immunosuppression loop in lung cancer as a strategy to prevent metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A05.
Abstract A13: Macrophage FLT1 mediated inflammatory response determines breast cancer distal metastasis
Authors: Qian Bin-Zhi , Zhang Hui , Li Jiufeng , Yeo Eun-Jin , Carragher Neil O. , Bresnick Anne R. , Lang Richard A. , Pollard Jeffrey W.
Published: May 2019

Macrophages are abundantly found in the tumor microenvironment and enhance malignancy. At distal metastatic sites, our previous studies identified a distinct population of metastasis associated macrophages (MAMs) that promotes tumor cell extravasation, seeding and persistent growth. These macrophages were derived from circulating inflammatory monocytes recruited by CCL2/CCR2 chemokine signaling and directly promote tumor cell extravasation and metastatic seeding in vivo through VEGF production. Our recent studies identified that MAMs express high levels of cell surface FMS-like tyrosine kinase 1 (FLT1, also known as VEGFR1) after their recruitment. Blockade of FLT1 signaling using specific inhibitory antibodies significantly inhibited the metastatic seeding and persistent growth. Using several genetic models of Flt1 deficiency, we show that macrophage specific FLT1 signaling is critical for breast tumor distal metastatic potential. FLT1 is not expressed by other hematopoietic cells and its inhibition did not affect the recruitment of MAMs, which indicated that specific FLT1 signaling in MAMs are important for their metastasis promoting functions. Indeed, we identified that FLT1 regulates a set of inflammatory response genes including Colony Stimulating Factor 1 (CSF1) a central regulator of macrophage biology. Using a genetic gain-of-function approach we show that CSF1 mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity in MAMs even when FLT1 has been inhibited. Together, our data established a link between inflammation and cancer metastasis and suggested the therapeutic potential of targeting these pathways in treating metastatic disease.

Citation Format: Bin-Zhi Qian, Hui Zhang, Jiufeng Li, Eun-Jin Yeo, Neil O. Carragher, Anne R. Bresnick, Richard A. Lang, Jeffrey W. Pollard. Macrophage FLT1 mediated inflammatory response determines breast cancer distal metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A13.
Abstract A15: SMC2 role in regulating tumor angiogenesis via FGF signaling
Authors: Sharif Ghada M. , Schmidt Marcel O. , Shuptrine Casey , Louis Weiner M. , Riegel Anna T. , Wellstein Anton
Published: May 2019

Fibroblast growth factors (FGFs) play a crucial role during embryonic development, tissue homeostasis, wound healing and angiogenesis. FGF-binding protein 1 (FGFBP1) is a secreted protein that binds FGFs stored in the extracellular matrix and transports them to their receptor, therefore they can modulate FGF signaling. FGFBP1 contributes to the progression of many cancers including colon, pancreas and squamous cell cancer. It acts as an angiogenic switch during tumor development. E0771 cells, a murine mammary carcinoma cell line, was subcutaneously injected into syngeneic C57BL/6 mice. While these cells form aggressive tumors within two weeks and metastasize to the lungs in wild type FGFBP1 (FGFBP1+/+) mice, there was no tumor growth or metastasis in FGFBP1 knock out (FGFBP1-/-) mice. A genome-wide shRNA library screen revealed a novel role for structural maintenance of the chromosome 2 (SMC2) in compensating for the loss of FGFBP1 in the stroma of FGFBP1-/- mice. E0771 cells with SMC2 knock down (KD) or CRISPR targeting SMC2 formed aggressive tumors in FGFBP1-/- mice and metastasized to the lungs. Surprisingly, FGFBP1 expression level was 32 folds lower in SMC2 KD E0771 cells yet FGF2 was 16 folds up in the tumors from SMC2 KD E0771 cells. Tumor histology shows impaired and leaky angiogenesis in FGFBP1-/- compared to FGFBP1+/+ mice. Furthermore, higher levels of GM-CSF and G-CSF were detected in the conditioned media (CM) of SMC2 KD E0771 cells compared to control cells suggesting differential immune cell recruitment. Also, an endothelial monolayer exposed to CM from SMC2 KD E0771 cells showed delayed wound closure and loose junctions suggesting a tendency for endothelium disintegration and initiation of blood vessel formation. Interestingly, the CM effect was blocked using PD173074, a pan FGFR inhibitor. In conclusion, SMC2 demonstrate a role in regulating FGF signaling which affects the course of angiogenesis during tumor development.

Note: This abstract was not presented at the conference.

Citation Format: Ghada M. Sharif, Marcel O. Schmidt, Casey Shuptrine, Weiner M. Louis, Anna T. Riegel, Anton Wellstein. SMC2 role in regulating tumor angiogenesis via FGF signaling. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A15.
Abstract A29: Gram-negative bacterial infection enhances the potential of gastric adenocarcinoma peritoneal metastasis via TNFR1 dependent manner
Authors: Alzahrani Malak , Giannias Betty , Bourdeau France , Kayano Rafael , Ferri Lorenzo
Published: May 2019

Adenocarcinoma of the proximal stomach is the fastest rising malignancy in North America, and is associated with a high rate of recurrence to the peritoneum. As part of cancer treatment, the majority of patients undergo at least one invasive surgical procedure. Recent clinical data has linked postoperative infection complications with adverse oncologic outcomes; however, the underlying mechanisms are unclear. Emerging evidence suggests that the release of TNFa, a key inflammatory cytokine during infection facilitates cancer progression. The role and mechanisms the gram-negative bacterial infections play in facilitating the metastatic potential of gastric cancer to the peritoneum is entirely unknown. We hypothesized that incubation of gastric cancer cells and MC with heat-inactivated E. Coli or LPS can augment gastric cancer cell adhesion and invasion via TNFR1 signaling and increase the potential of peritoneal metastasis. Incubation of human gastric cancer cells or/and MC with heat inactivated E. coli, LPS or TNFa significantly increased in vitro adhesion 3-4 folds to MC and enhanced in vitro invasion. These enhanced cell adhesion and invasion phenotypes following incubation with LPS or E. coli were attenuated at three levels: inhibition of TLR4 (Eritoran), inhibition of TNFR1 (anti-TNFR1/isotype control antibodies) or p38 MAPK inhibitor (BIRB0796). TNFa treatment also increases CD54, CD44 and CD29 expression on cancer cells and MC. To further validate in vitro results, a novel ex-vivo murine peritoneal metastasis model is developed. We report that ex vivo gastric cancer cells adhesion to murine peritoneum is augmented by overnight LPS, E. Coli and TNFa treatments and this effect was abrogated when TNFR1-/- mouse peritoneum is used or in the presence of TNFR1 monoclonal or isotype control antibodies. These findings implicate TNFa in the process of gastric cancer metastasis to peritoneum in the context of systemic infection and identify TNFa as potential therapeutic targets.

Citation Format: Malak Alzahrani, Betty Giannias, France Bourdeau, Rafael Kayano, Lorenzo Ferri. Gram-negative bacterial infection enhances the potential of gastric adenocarcinoma peritoneal metastasis via TNFR1 dependent manner. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A29.
Abstract A36: Function of GPR56 in metastasis dormancy of melanoma
Authors: Corson Nancy , Warren Michelle , Xu Lei
Published: May 2019

Dormancy imposes significant challenges for cancer diagnosis and prognosis. We use pairs of metastatic melanoma cell lines that have different abilities to form metastases to investigate the molecular mechanisms of metastatic dormancy. We found that a novel receptor, GPR56, was down-regulated in highly metastatic melanoma cells compared with the poorly metastatic parental line. Re-expression of GPR56 in five different melanoma cell lines resulted in inhibition of metastasis formation in mouse lung. RNAseq analyses revealed that GPR56 might regulate the expression of genes involved in cellular homeostasis. Furthermore, our preliminary data show that GPR56 internalizes and degrades its ligand, TG2 from cell surface. TG2 is an ECM protein and functions to stabilize ECM and facilitate its signaling. The loss of TG2 resulting from GPR56 expression would disrupt ECM deposition and signaling in melanomas, ultimately leading to disturbance of cellular homeostasis of melanoma cells and their growth arrest. Taken together, we propose a model in which the novel receptor GPR56 sequesters metastatic melanomas at dormant states by down-regulating TG2 from cell surface and modulating cellular homeostasis.

Citation Format: Nancy Corson, Michelle Warren, Lei Xu. Function of GPR56 in metastasis dormancy of melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A36.
Abstract A38: A PERK inhibitor that blocks HER2-driven tumorigenesis and suppresses metastasis by targeting single disseminated tumor cells
Authors: Calvo Veronica , Staschke Kirk A. , Paredes Maria Cristina Garcia , Avivar-Valderas Alvaro , Cheung Julie , Wild Robert , Rigby Alan C. , Farias Eduardo F. , Aguirre-Ghiso Julio
Published: May 2019

The unfolded protein response (UPR) is a critical survival and adaptation pathway in cancer cells. The endoplasmic reticulum kinase PERK serves as a survival UPR factor for different tumor types, including those driven by the oncogene HER2, and it can also promote survival of dormant cancer cells. We wanted to evaluate the effect of a potent and selective new PERK inhibitor (LY4) on MMTV-HER2-driven tumorigenesis that, through genetic experiments, was shown to depend on a full complement of PERK for progression. Here we show that, from ductal carcinoma in situ (DCIS) through invasive cancer, MMTV-HER2-driven tumors and also HER2+ human cancer cell lines are exquisitely sensitive to this novel PERK inhibitor. We found that early MMTV-HER2+ lesions require PERK for HER2-driven alterations in ductal epithelial organization, and that LY4 impairs the expansion of established HER2+ tumor cells in 3D organotypic cultures and in vivo. Importantly, PERK inhibition blunted metastasis development. This effect was linked to the ability of the PERK inhibitor to eradicate solitary HER2+ disseminated tumor cells that, in their majority, are dormant or slow-cycling, but that represent the seeds for further metastases. Mechanism analyses revealed that PERK inhibition indirectly blocked the phosphorylation of HER2 and EGFR and their downstream signaling activation in response to EGF, possibly by altering receptor protein quality control. Our data suggest that in HER2-driven cancers PERK inhibition might be a novel therapeutic strategy to treat primary and metastatic lesions.

Citation Format: Veronica Calvo, Kirk A. Staschke, Maria Cristina Garcia Paredes, Alvaro Avivar-Valderas, Julie Cheung, Robert Wild, Alan C. Rigby, Eduardo F. Farias, Julio Aguirre-Ghiso. A PERK inhibitor that blocks HER2-driven tumorigenesis and suppresses metastasis by targeting single disseminated tumor cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A38.
Abstract A41: Elucidating candidate biomarkers of breast cancer progression and dormancy using a 3D model of metastasis
Authors: Clark Amanda M. , Wheeler Sarah E. , Young Carissa L. , Pillai Venkateswaran C. , Stolz Donna B. , Lauffenburger Douglas A. , Venkataramanan Raman , Griffith Linda G. , Wells Alan
Published: May 2019

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR11) of the Conference Proceedings.

Citation Format: Amanda M. Clark, Sarah E. Wheeler, Carissa L. Young, Venkateswaran C. Pillai, Donna B. Stolz, Douglas A. Lauffenburger, Raman Venkataramanan, Linda G. Griffith, Alan Wells. Elucidating candidate biomarkers of breast cancer progression and dormancy using a 3D model of metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A41.
Abstract A60: Loss of α3 integrin expression promotes α6 integrin internalization to Rab4 vesicles and migration of human prostate cancer cells
Authors: Das Lipsa , Anderson Todd A. , Gard Jaime M. , Sroka Isis C. , Strautman Stephanie R. , Nagle Raymond B. , Morrissey Colm , Knudsen Beatrice S. , Cress Anne E.
Published: May 2019

Background: Metastatic prostate cancer express laminin binding integrins α6 and α3 while losing the expression of a variety of integrins present in normal prostate gland.

Results: In human xenograft tissues, at least 70% of bone and soft tissue metastasis of prostate cancer (185 samples from 45 patients) had cytoplasmic expression of the α6 integrin that correlated to increased expression of intracellular trafficking proteins. Given the reported link between cytoplasmic integrin distribution and integrin endocytosis, surface labelled integrin α6 were quantified for internalization kinetics using flow cytometry. The integrin α6 was internalized 3-fold faster than α3 integrin (CD49c) (1.0 min-1), 1.5-fold faster than the vitronectin binding αv integrin (CD51) (2.2 min-1), and significantly slower than the unrelated transferrin receptor (TfR, CD71) (15 min-1).

Silencing α3 expression increased α6 integrin internalization by 1.45 fold without affecting internalization of non-integrin control receptor, TfR. The internalized α6 integrin was targeted to early endosomes and Rab4 recycling vesicles and redistributed to a cell-cell staining pattern similar to human prostate cancer specimens. This was accompanied by a 1.8-fold increase in cancer cell migration that was dependent on α6 integrin. Silencing integrin α6 however, didn't affect the internalization rate or intracellular endocytic distribution of the α3 integrin.

Conclusion and Significance: We conclude that internalization of the α6 and α3 integrins is coordinated in a unidirectional fashion and their relative expression can significantly modulate cancer cell migration. The observed loss of α3 integrin expression in high grade cancer is predicted to increase the internalization and pro-migratory features of α6 integrin in high grade cancer.

Acknowledgements: Research was supported in part by NIH research grants R01 CA 159406, CA 23074 and CA09213. Patient tissue studies were supported by Biobank and Translational Research Core, Cedars Sinai Medical Center, CA, Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grants (PO1CA085859) and the Richard M. LUCAS Foundation.

Citation Format: Lipsa Das, Todd A. Anderson, Jaime M. Gard, Isis C. Sroka, Stephanie R. Strautman, Raymond B. Nagle, Colm Morrissey, Beatrice S. Knudsen, Anne E. Cress. Loss of α3 integrin expression promotes α6 integrin internalization to Rab4 vesicles and migration of human prostate cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A60.
Abstract B05: Repurposing FDA-approved drugs for anti-metastatic therapy: Results of an integrated genome wide screen for metastasis modifiers
Authors: Shukla Anjali , Hunter Kent W.
Published: May 2019

Metastasis remains the primary cause of patient morbidity and mortality in solid tumors. Recent advances in genomic technologies have provided major insights into the etiology of tumors. However, significantly less is known about factors that contribute to metastasis. Here we report the results of a genome-wide integrated genetic, transcriptional, and epigenetic analysis in a mouse mammary tumor model to identify factors associated with tumor progression. This strategy identified a prognostic transcription signature and several upstream transcriptional regulators for metastatic disease. Interestingly, this analysis also identified novel or other FDA-approved drugs as potentially useful for anti-metastatic therapy. As predicted by this screen, administration of antidiabetic thiazolidones Rosiglitazone and Pioglitazone suppressed metastasis in an orthotopic breast cancer mouse model. Similarly, ciprofloxacin, an antibiotic, also decreased breast cancer metastasis. This strategy is thus not only of prognostic value but also presents the opportunity to rapidly repurpose drugs with proven safety and efficacy profiles for control and treatment of advanced neoplastic disease.

Citation Format: Anjali Shukla, Kent W. Hunter. Repurposing FDA-approved drugs for anti-metastatic therapy: Results of an integrated genome wide screen for metastasis modifiers. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B05.
Abstract B19: The histone demethylase KDM3A in Ewing sarcoma metastasis
Authors: Sechler Marybeth , Parrish Janet , Jedlicka Paul
Published: May 2019

This study aims to explore the roles and mechanisms of new candidates for therapeutic targeting in Ewing Sarcoma. Ewing Sarcoma is an aggressive pediatric malignancy of the bone and soft tissue, driven by EWS/Ets oncogenic fusions and characterized by high propensity for metastasis and poor clinical outcomes. We have identified the histone demethylase KDM3A as a novel tumor and metastasis promoter downstream of EWS/Fli1, the most common driver in this disease. Moreover, we have identified the cell surface protein, Melanoma Cell Adhesion Molecule (MCAM), as a potential important mediator of KDM3A action. Our data show that both KDM3A and MCAM depletion can inhibit metastatic phenotypes. Additionally we explore the regulation of MCAM, showing that KDM3A may upregulate MCAM expression both through a direct as well as an indirect mechanism via the Ets1 transcription factor. Since both KDM3A and MCAM are pharmacologically targetable, understanding of this pathway could provide at least two new therapeutic targets in Ewing Sarcoma, and, importantly alternatives to drugging of EWS/Ets fusions, which to date has proven very difficult.

Citation Format: Marybeth Sechler, Janet Parrish, Paul Jedlicka. The histone demethylase KDM3A in Ewing sarcoma metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B19.
Abstract B22: Loss of LncRNA XIST induces Epithelial to Mesenchymal Transition in Breast Cancer
Authors: Liu Yin , Xing Fei , Wu Kerui , Sharma Sambad , Watabe Kounosuke
Published: May 2019

Brain is one of the major sites of metastasis of breast cancer, and approximately 20% of patients with aggressive breast cancer eventually develop the metastatic disease in the brain. Long non-coding RNAs (lncRNA) have recently drawn much attention due to their wide functional variations and potential roles in tumor progression. By performing lncRNA array analysis comparing non-metastatic primary tumors with brain metastatic tumors from breast cancer patients, we identified that lncRNA XIST expression was significantly down-regulated in brain metastatic tumors. The result of Taqman PCR validated the results in tumor samples and also indicated that XIST expression was down-regulated in brain metastatic cell lines compared to non-brain metastatic cell lines. Moreover, we found that the XIST expression was negatively correlated with breast cancer stage and brain metastasis-free survival. XIST is located on the q arm of the X chromosome (Xq13-2) and plays a critical role in the X inactivation, thus providing dosage equivalence between males and females. Importantly, XIST has been found to be down-regulated in several types of tumors including breast cancer. Loss of XIST facilitates escape of some X chromosome genes from inactivation. To further study the effect of XIST down-regulation on tumor cells, we knocked down XIST expression in MCF7 by siRNA. We found that the knockdown of XIST drastically altered the morphology of MCF7 cell from epithelial to mesenchymal type. Furthermore, several epithelial-mesenchymal transition (EMT)-related genes including ZEB2 and SNAIL were upregulated in the XIST knockdown cells. In addition, the results of qPCR, western blot and immunocytochemical analysis showed that the epithelial marker E-cad was significantly down-regulated, while mesenchymal markers N-cad and Vimentin were upregulated in MCF7-siXIST, SKBR-siXIST and ZR751-siXIST cells compared to the control cells. To further examine the effect of XIST knockdown in vivo, we transplanted MCF7-siXIST, SKBR3-siXIST and their control cells by intra-cardiac injection into nude mice. We found that knockdown of XIST significantly enhanced tumor metastasis, especially in the brain. Our results strongly suggest that lncRNA XIST plays a critical role in tumor progression and metastasis by inducing EMT.

Citation Format: Yin Liu, Fei Xing, Kerui Wu, Sambad Sharma, Kounosuke Watabe. Loss of LncRNA XIST induces Epithelial to Mesenchymal Transition in Breast Cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B22.
Abstract B35: NR2F1 limits early dissemination and phenotypic plasticity of early-progressed ErbB2+ tumor cells by maintaining luminal differentiation
Authors: Sosa Maria Soledad , Cheung Julie , Aguirre-Ghiso Julio A.
Published: May 2019

Tumor cells derived from MMTV-Neu primary tumors (tumor-derived cells, TDC) are known to be able to complete all steps of the metastatic cascade. However, new evidence shows that cells derived from early stages of tumor progression (before detection of palpable tumors, ErbB2+ early-progressed tumor cells, EPTC) can disseminate and, as disseminated tumor cells (early DTCs), enter a non-proliferative state for prolonged periods at secondary organs. When EPTC are co-cultured with TDC, the tumor sphere formation capacity of the later is increased suggesting a synergistic contribution of early-progressed tumor cells to the growth of TDC. Thus, early DTCs are proposed to contribute to metastasis, but the mechanisms that would allow these cells, considered sessile and with few genetic alterations, to complete all steps of metastasis are unknown. Here we report that the orphan nuclear receptor NR2F1 is downregulated in human pre-malignant and malignant lesions and mouse ErbB2+ EPTC and TDC when compared with normal mammary tissue. In ErBb2+ EPTC further downregulation of NR2F1 activates a motile phenotype and this is coincident with the detection of circulating tumor cells (CTCs) and DTCs in lungs and bone marrow. Knock down of basal NR2F1 levels in ErBb2+ EPTC induced cell motility, loss of laminin-V deposition, β-catenin delocalization from the membrane and dramatic loss of E-cadherin junctions. Interestingly, TWIST, SMAD2, CK14 and ROR1 levels became upregulated upon NR2F1 depletion. This anti-EMT NR2F1-regulated program is ErbB2 oncogen-dependent. These results suggest that NR2F1 expression maintains epithelial identity and suppresses epithelial-mesenchymal transition (EMT), possibly by blocking WNT signaling. Knock down of NR2F1 in ErBb2+ EPTC also enhanced mammosphere formation efficiency and this was accompanied by upregulation of the pluripotency transcription factor NANOG and TWIST. These findings suggest that NR2F1 limits the spreading of ErBb2+ EPTC cells and it promotes a luminal differentiation-associated program by limiting the activation of a stem cell-like program. Our findings provide for the first time evidence that NR2F1 functions in mammary epithelial cells as a suppressor of pluripotency and dissemination during early stages of tumor progression. We propose that therapies that might restore expression of NR2F1 might limit early dissemination and the progression to metastasis of already disseminated tumor cells.

Citation Format: Maria Soledad Sosa, Julie Cheung, Julio A. Aguirre-Ghiso. NR2F1 limits early dissemination and phenotypic plasticity of early-progressed ErbB2+ tumor cells by maintaining luminal differentiation. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B35.
Abstract B41: Haptotaxis and direct remodeling of the extracellular matrix by tumor cells is important for metastasis
Authors: Oudin Madeleine J. , Jonas Oliver , Kosciuk Tatiana , Broye Liliane , Wyckoff Jeff , Klazen Joelle , Lamar John , Asokan Sreeja , Whittaker Charlie , Langer Robert , Cima Michael , Wisinski Kari , Hynes Richard , Lauffenburger Douglas , Keely Patricia , Bear James , Gertler Frank
Published: May 2019

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR15) of the Conference Proceedings.

Citation Format: Madeleine J. Oudin, Oliver Jonas, Tatiana Kosciuk, Liliane Broye, Jeff Wyckoff, Joelle Klazen, John Lamar, Sreeja Asokan, Charlie Whittaker, Robert Langer, Michael Cima, Kari Wisinski, Richard Hynes, Douglas Lauffenburger, Patricia Keely, James Bear, Frank Gertler. Haptotaxis and direct remodeling of the extracellular matrix by tumor cells is important for metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B41.
Abstract B43: ADAM12 is a novel regulator of stem-like cells in triple-negative breast cancer
Authors: Qi Yue , Duhachek-Muggy Sara , Li Hui , Alyahya Linda , Wise Randi , Zolkiewska Anna
Published: May 2019

High expression of metalloprotease ADAM12 is associated with increased metastasis in triple-negative breast cancers (TNBC) and is an independent prognostic factor of chemoresistance in TNBC. ADAM12 is up-regulated in the claudin-low subtype of breast tumors and in the mesenchymal stem-like subtype of TNBC. Furthermore, expression of ADAM12 is elevated in post-therapy tumors. The goal of our study was to examine whether ADAM12 may serve as a marker or a therapeutic target in cells with enhanced metastatic cancer stem cell phenotype, using two representative TNBC cell lines with aggressive and metastatic phenotype, SUM159PT and Hs578T. We found that sorted cell subpopulations with the highest cell surface expression of ADAM12 had increased expression of cancer stem cell markers, decreased proliferation rates in 2-D cultures, and increased ability to form mammospheres under suspension conditions. ADAM12 knockdown decreased mammosphere formation, increased apoptotic cell death upon detachment, and decreased cell migration and invasion. ADAM12 knockdown also decreased the population of CD44+/CD24- cells and ALDEFLUOR+ cells and reduced tumor formation in mice in vivo, suggesting that ADAM12 might be necessary for maintaining cancer stem cell phenotype of TNBC cells. To get insight into molecular pathways modulated by ADAM12, we performed RNA sequencing in cells with inducible knockdown of ADAM12 and identified several candidate pathways. Our results indicate that ADAM12 is a novel regulator of the plasticity of TNBC stem cells and it may serve as a future target in anti-metastatic breast cancer therapies.

Citation Format: Yue Qi, Sara Duhachek-Muggy, Hui Li, Linda Alyahya, Randi Wise, Anna Zolkiewska. ADAM12 is a novel regulator of stem-like cells in triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B43.