bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P6-09-08: High circulating levels of Periostin are associated with a poor survival in primary, non-metastatic breast cancer patients
Authors: Hoffmann O , Goebel A , Bittner A-K , Rauner M , Hofbauer LC , Kimmig R , Kasimir-Bauer S , Rachner TD
Published: May 2019

Background: Periostin, also known as osteoblast-specific factor OSF-2, functions as a ligand for integrins to support adhesion and migration of tumor cells which leads to increased cell survival, invasion, angiogenesis and metastasis in different cancer types including breast cancer (BC). Assuming that metastasis requires a dissemination of tumor cells, associated with worse outcome in BC, the aim of this study was to determine the expression of Periostin in blood samples of patients with primary, non-metastatic BC and to correlate the results with clinical parameters including the presence of disseminated tumor cells (DTCs) in the bone marrow (BM), survival and the risk of developing metastatic disease.

Patients and Methods: BM and blood sampling were performed before surgery in an adjuvant setting in 509 patients with first diagnosis of BC between Aug 2006 and Dec 2009. Two BM aspirates were analyzed for DTCs using density centrifugation followed by immunocytochemistry applying the pan-cytokeratin antibody A45-B/B3. Blood was collected from each patient and Periostin serum levels were measured by ELISA (Biomedica, Vienna, Austria).

Results: Periostin levels were detectable (504.8 ± 178.7 pmol/l) in all BC patients. There were no significant differences between serum Periostin levels when stratifying according to tumor stage, lymph node involvement or grading. Periostin levels were significantly increased in women above the age of 60 (468.6±166.6 pmol/l vs. 540.1±184.2 pmol/l; p<0.0001) and significantly enhanced in postmenopausal compared to peri- or premenopausal women (p<0.05 and p<0.001, respectively). No differences were observed between DTC-positive and DTC-negative patients. When separating patients according to high (top 50%) or low (low 50%) Periostin levels, patients with low Periostin levels had a significantly shorter BC specific survival (HR 0.61; 95%CI 0.39-0.96; p=0.03).

Conclusion: In summary, while Periostin levels were unchanged in patients with and without DTCs, high levels of Periostin were associated with a poorer BC specific survival. These results warrant further studies on the role of Periostin in BC.

Citation Format: Hoffmann O, Goebel A, Bittner A-K, Rauner M, Hofbauer LC, Kimmig R, Kasimir-Bauer S, Rachner TD. High circulating levels of Periostin are associated with a poor survival in primary, non-metastatic breast cancer patients [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 P6-09-08.
Abstract P6-10-01: Consumption of sugar-containing beverages and cancer risk: Results from the NutriNet-Santé prospective cohort
Authors: Chazelas E , Srour B , Desmetz E , Kesse-Guyot E , Julia C , Druesne-Pecollo N , Galan P , Zelek L , Hercberg S , Latino-Martel P , Deschasaux M , Touvier M
Published: May 2019

OBJECTIVE

To assess the associations between the consumption of sugar-containing and artificially sweetened beverages and cancer risk.

DESIGN

Population based prospective cohort study.

SETTING AND PARTICIPANTS

Overall, 101 257 participants aged ≥18y (mean age: 42.2±14.4y) from the French NutriNet-Santé cohort (2009-2017) were included. Consumptions of sugar-containing and artificially sweetened beverages were assessed using repeated 24h-dietary records, designed to register participants' usual consumption for 3300 different food and beverage items.

MAIN OUTCOME MEASURES

Associations between beverage consumption and overall, breast, prostate and colorectal cancer risk were assessed by multivariable Cox Proportional Hazard models adjusted for known risk factors.

RESULTS

A 100mL increase in the consumption of sugar-containing beverages was significantly associated with an increased risk of overall cancer (HR=1.08, 95% confidence interval 1.04 to 1.12, P<.0001) and breast cancer (HR=1.11, 95% confidence interval 1.04 to 1.19, P<0.002). The consumption of artificially sweetened beverages was not associated with cancer risk. In sub-analyses, a 100 mL increase in the consumption of 100% fruit juice was significantly associated with an increased risk of overall cancers (HR=1.08, 95% confidence interval 1.02 to 1.15, P=0.01). These associations were strongly mediated by the sugar contained in these beverages. In contrast, weight gain during follow-up did not appear as a strong mediator. Besides, results were similar in overweight and non-overweight participants.

CONCLUSIONS

In this large prospective study, a 100mL increase in the consumption of sugar-containing beverages in the diet was associated with an 8% significant increase in overall cancer risk and an 11% significant increase in breast cancer risk. 100% fruit juices were also associated with an 8% increased risk of overall cancers. Given the massive consumption of sugar-containing beverages in Western countries, these results suggest that they may represent a key modifiable risk factor for cancer prevention.

Citation Format: Chazelas E, Srour B, Desmetz E, Kesse-Guyot E, Julia C, Druesne-Pecollo N, Galan P, Zelek L, Hercberg S, Latino-Martel P, Deschasaux M, Touvier M. Consumption of sugar-containing beverages and cancer risk: Results from the NutriNet-Santé prospective cohort [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 P6-10-01.
Abstract P6-10-02: Not presented
Authors: McDonnell SL , Baggerly CA , French CB , Baggerly LL , Garland CF , Gorham ED , Lappe JM
Published: May 2019

This abstract was not presented at the conference.

Citation Format: McDonnell SL, Baggerly CA, French CB, Baggerly LL, Garland CF, Gorham ED, Lappe JM. Not presented [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 P6-10-02.
Abstract P6-14-02: Withdrawn
Authors: Esser MR , Rowe JJ , McCann ML , Nicholas-Alexander M , Helck EP , Lewis SM
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Esser MR, Rowe JJ, McCann ML, Nicholas-Alexander M, Helck EP, Lewis SM. 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 P6-14-02.
Abstract P6-17-34: Not presented
Authors: Yang F , Yin Y , Jiang Z
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Yang F, Yin Y, Jiang Z. Not presented [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 P6-17-34.
Abstract P6-18-27: Withdrawn
Authors: Odom D , Mitra D , Hollis K , Richardson D , Kaye JA , McRoy L
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Odom D, Mitra D, Hollis K, Richardson D, Kaye JA, McRoy L. 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 P6-18-27.
Abstract P6-21-04: Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss
Authors: Owusu-Brackett N , Zhao M , Akcakanat A , Evans KW , Yuca E , Tapia C , Ileana-Dumbrava E , Janku F , Meric-Bernstam F
Published: May 2019

Background: PTEN functions as a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway to promote balanced cell proliferation, survival and differentiation. PTEN loss occurs across a variety of cancer subtypes; PTEN-deficient tumors are dependent on PI3Kβ activity, making PI3Kβ a compelling target. We evaluated the efficacy of PI3Kβ inhibitor AZD8186 as a single agent and in combination with standard chemotherapy and immune checkpoint inhibitors focused on tumors with loss of PTEN function.

Methods: In vitro, cell proliferation assays were performed to determine the half maximal inhibitory concentration (IC50) after 3 days of treatment and to test the effects in combination with standard chemotherapy. Colony formation assays were performed to confirm efficacy of AZD8186 in PTEN-deficient cell lines. Western blot analysis was performed to assess PTEN protein expression and to evaluate effects of AZD8186 on PI3K signaling. In vivo, antitumor efficacy of AZD8186 as a single agent as well as in combination with paclitaxel and anti-PD1 was evaluated.

Results: AZD8186 inhibited the cell proliferation of three of ten TNBC cell lines in vitro; PTEN loss was significantly correlated with AZD8186 sensitivity (p= 0.008). Colony formation assay confirmed sensitivity of PTEN-deficient cell lines to AZD8186. AZD8186 inhibited PI3K signaling with decreased expression of pAKT, pGSK3β, pPRAS40 and pS6. AZD8186 treatment of PTEN-deficient cell lines, MDA-MB-436 and MDA-MB-468, resulted in increased apoptosis. Cell proliferation assays demonstrated additive effect of the combination of paclitaxel with AZD8186. AZD8186 significantly enhanced antitumor activity of paclitaxel in MDA-MB-436 and MDA-MB-468 cell-line-derived xenografts, with disease stabilization in the latter. In syngeneic models, AZD8186 enhanced antitumor efficacy of anti-PD1 antibodies in PTEN-deficient BP murine melanoma xenograft (p=0.0073), but not in PTEN-wildtype colon carcinoma, CT26.

Conclusion: AZD8186 has single agent efficacy in PTEN-deficient triple negative breast cancer cell lines in vitro, with modest single agent efficacy in vivo. AZD8186 enhanced the antitumor efficacy of paclitaxel and of Anti-PD1 antibodies in vivo. Further study is needed to determine optimal combination therapies for PTEN-deficient solid tumors.

Citation Format: Owusu-Brackett N, Zhao M, Akcakanat A, Evans KW, Yuca E, Tapia C, Ileana-Dumbrava E, Janku F, Meric-Bernstam F. Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss [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 P6-21-04.
Abstract P6-21-10: Not presented
Authors: Pacaud R , Thomas S , Roche E , Pawlowska N , Munster P
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Pacaud R, Thomas S, Roche E, Pawlowska N, Munster P. Not presented [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 P6-21-10.
Abstract PD1-02: Withdrawn
Authors: Cortes J , Martin M , Pernas S , Gomez Pardo P , Lopez-Tarruella S , Gil-Martin M , Manso L , Ciruelos E , Perez-Fidalgo JA , Hernando C , Ademuyiwa FO , Weilbaecher K , Mayer I , Pluard TJ , Martinez Garcia M , Vahdat L , Wach A , Barker D , Romagnoli B , Kaufman PA
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Cortes J, Martin M, Pernas S, Gomez Pardo P, Lopez-Tarruella S, Gil-Martin M, Manso L, Ciruelos E, Perez-Fidalgo JA, Hernando C, Ademuyiwa FO, Weilbaecher K, Mayer I, Pluard TJ, Martinez Garcia M, Vahdat L, Wach A, Barker D, Romagnoli B, Kaufman PA. 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 PD1-02.
Abstract PD1-12: Omics profiling of CDK4/6 inhibitors reveals functionally important secondary targets of abemaciclib
Authors: Mills CE , Hafner M , Subramanian K , Chen C , Chung M , Boswell SA , Everley RA , Walmsley CS , Juric D , Sorger PK
Published: May 2019

The recent introduction of small molecule inhibitors of cyclin-dependent kinases (CDK) 4/6 to the clinic has improved the treatment of hormone receptor positive breast cancer, and shown promise in other malignancies. The three clinically used CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are reported to be broadly similar although recent data suggest that abemaciclib has distinct single-agent activity in patients and a unique adverse effects profile. Key questions are: How do these drugs differ at the molecular level? Should such differences inform their use in the clinic? Can these three agents be used interchangeably or should patient stratification differ between them? We use molecular and functional profiling by mRNA sequencing, mass spectrometry-based proteomics, and GR-based dose-response assays to obtain complementary views of the mechanisms of action of CDK4/6 inhibitors. We show that abemaciclib, but not ribociclib or palbociclib, is a potent inhibitor of kinases other than CDK4/6, including CDK1/Cyclin B, which appears to cause arrest in the G2 phase of the cell cycle, and CDK2/Cyclin E/A, which is implicated in resistance to palbociclib. We show that inhibition of these additional targets is accessible in a xenograft model. Whereas ribociclib and palbociclib induce cytostasis, and cells adapt to these drugs within 2-3 days of exposure, abemaciclib induces cell death and durably blocks cell proliferation. Abemaciclib is active even in retinoblastoma protein (pRb)-deficient cells in which CDK4/6 inhibition by palbociclib or ribociclib is completely ineffective. The degree of polypharmacology of small molecule drugs is increasingly viewed as an important consideration in their design, with implications for efficacy, toxicity, and acquired resistance. In the case of CDK4/6 inhibitors, we propose that abemaciclib polypharmacology elicits unique molecular responses. More generally, we propose that multi-omic approaches are required to fully elucidate the spectrum of targets relevant to drug action in tumor cells. We expect such understanding to assist in stratifying patient populations and ordering sequential therapies when resistance arises.

Citation Format: Mills CE, Hafner M, Subramanian K, Chen C, Chung M, Boswell SA, Everley RA, Walmsley CS, Juric D, Sorger PK. Omics profiling of CDK4/6 inhibitors reveals functionally important secondary targets of abemaciclib [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 PD1-12.
Abstract PD4-01: A new additive diagnostic assay for breast cancer screening - Biochemical infrared analysis of immune cells and plasma
Authors: Allweis TM , Schmitt J , Zelig U
Published: May 2019

Background:

Screening for early detection of breast cancer is currently based on breast imaging. Screening mammography, the most commonly used imaging modality, has limited sensitivity, especially in dense breast tissue, and a significant rate of false positive results. An adjuvant blood-test based assay may improve breast cancer detection irrespective of breast density. In previously reported studies, Total Biochemical Infrared Analysis (TBIA) of peripheral blood mononuclear cells (PBMCs) and plasma was able to differentiate between patients with breast cancer and healthy controls or patients with benign breast disease. The TM-B1TM assay is based on TBIA technology and is intended for breast cancer screening. In the present study, the performance of the TM-B1TM assay was evaluated for cancer detection across breast densities.

Patients and Methods:

A total of 220 women were recruited to this IRB approved study: 50 women with newly diagnosed breast cancer, and two control groups – 79 patients with benign findings and 61 patients with no detectable abnormality. Twenty-nine women were withdrawn from the study (for eligibility or technical reasons), and the data presented refer to 190 cases. Breast cancer patients included 6 cases of DCIS, 1 of LCIS, 42 of IDC and 1 of ILC. Ten milliliters of blood were drawn and separated by Ficoll gradient method into PBMCs and plasma. The samples were dried on a zinc selenide optical window and analyzed by a FTIR spectrometer. The spectra were analyzed by the proprietary software TodoSpectra to distinguish between infrared spectra of cancer patients vs. patients with benign findings and healthy controls. The influence of age and breast density on TM-B1TM results were evaluated.

Results:

The TM-B1 assay obtained a sensitivity of 86 % and specificity of 98 % for breast cancer detection. The positive predictive value (PPV) was 95.1% and the negative predictive value (NPV) was 93.5%. Dense breast tissue (BIRADS categories C&D) was present in 55 % of the subjects. The specificity and sensitivity for patients with dense breasts was 99 % and 83 % respectively. No major differences in accuracy of TM-B1 were found due to patients' age.

Conclusions:

TM-B1 in conjunction with current imaging techniques may contribute to early detection of breast cancer by increasing sensitivity and reducing false positive results and unnecessary biopsies. Further studies with larger patient numbers are required and under way to establish the utility of adding the TM-B1 assay to current standard screening for breast cancer.

Citation Format: Allweis TM, Schmitt J, Zelig U. A new additive diagnostic assay for breast cancer screening - Biochemical infrared analysis of immune cells and plasma [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 PD4-01.
Abstract PD4-12: Use of 64Cu-DOTA-trastuzumab positron emission tomography (PET) to predict response to ado-trastuzumab emtansine (TDM1)
Authors: Mortimer JE , Bading JR , Frankel P , Tumyan L , Tran TT , Rockne RC , Shively JE , Gidwaney N , Park J , Colcher DM
Published: May 2019

Background: We have demonstrated that 64Cu-DOTA trastuzumab is an effective PET imaging agent for HER2 positive breast cancer and are now seeking to evaluate the methodology for prediction of response and benefit to ado-trastuzumab emtansine (TDM1) in women with metastatic disease.

Methods: Patients with metastatic breast cancer were eligible if they had biopsy confirmed HER2 + disease, at least 1 site of metastasis 2.0 cm or larger outside the biopsy site, and were to receive TDM1 as therapy. Pretreatment staging included 18F-FDG/PET. Prior to injection of 64Cu-DOTA-trastuzumab, patients received 45 mg of cold trastuzumab to reduce liver uptake. PET-CT scans were obtained at 21-25 h and 47-48 h over fields of view chosen in reference to 18F-FDG scans. TDM1 was administered at a dose of 3.6 mg/kg every 3 weeks. Restaging 18F-FDG/PET was performed every 2 cycles, and response to therapy was determined by PERCIST criteria. The radiolabel uptake was measured in terms of maximum voxel standardized uptake value (SUVmax).

Results: Ten women enrolled on study and are evaluable for response; three continue on TDM1 for 22-40 months and four patients remained on treatment for at least 1 year. The median age was 54.5 years (48-83 years); seven received prior trastuzumab-containing chemotherapy 3 wks to 55 months prior to study entry. HER2 was positive by IHC in 5 and by FISH in 5 (3 were 2+ by IHC; 1 was 1+ and 1 indeterminate). Complete or partial metabolic response was observed in 5 patients. Patients had their average SUVmax on 64Cu-DOTA trastuzumab PET (aSUVmax) assessed in addition to individual assessments on up to 8 lesions on both Day1 and Day2. The mean aSUVmax was (6.3, 8.8) for responding patients and (4.4, 5.2) for non-responder (day1, day2). The difference between responders and non-responders on Day1 aSUVmax was marginally significant (p=0.06), but significant on Day2 (p=0.04). The three highest aSUVmax on both day1 and day2 were three of the four patients with PFS>1 year. Data on the relationship of 64Cu-DOTA trastuzumab PET to IHC and FISH, and individual lesion SUVmax including evidence suggesting a potential threshold effect will be presented.

Conclusions: In women with biopsy confirmed HER2 positive metastatic disease, 64Cu-DOTA-trastuzumab PET imaging is predictive for response to TDM1.

Citation Format: Mortimer JE, Bading JR, Frankel P, Tumyan L, Tran TT, Rockne RC, Shively JE, Gidwaney N, Park J, Colcher DM. Use of 64Cu-DOTA-trastuzumab positron emission tomography (PET) to predict response to ado-trastuzumab emtansine (TDM1) [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 PD4-12.
Abstract TS2-1: The complexity of targeting PI3K for cancer therapy
Authors: Cantley L
Published: May 2019

Phosphoinositide 3-Kinase (PI3K) is activated by insulin and other growth factors to mediate cell growth. The PI3K enzyme encoded by the PIK3CA gene is one of the most frequently mutated oncogenes in human cancer. This same enzyme mediates insulin responses in liver, muscle, fat and other tissues. The most common mutations in this gene enhance the ability of PI3K to be activated by insulin. Since breast cancers typically express relatively high levels of the insulin receptor, high serum insulin levels are likely to enhance activation of PI3K in breast cancers. PI3K inhibitors that target PIK3CA have the expected physiological effect of raising serum glucose and insulin levels and the elevated insulin is likely to compromise the effectiveness of therapy. Data will be presented showing that in mouse models of human breast cancers and other cancers, dietary interventions and pharmaceutical interventions that limit elevation of serum insulin during PI3K therapy improve responses to PI3K inhibitors.

Citation Format: Cantley L. The complexity of targeting PI3K for cancer therapy [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 TS2-1.
Abstract TS3-2: Modulation of anti-tumor immunity using CDK4/6 inhibitors
Authors: Goel S
Published: May 2019

Several pharmacological inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have now been approved for the treatment of metastatic estrogen receptor-positive breast cancer. Although CDK4/6 inhibitors were initially developed to prevent cancer cell proliferation, preclinical studies have now demonstrated that they can also exert other biological effects in solid tumors including augmentation of anti-tumor immunity. The detailed mechanisms underlying this are currently under investigation, and likely include enhanced antigen presentation by tumor cells as well as an increase in the ratio of effector to regulatory T lymphocytes. In this presentation, I will discuss our current understanding of how CDK4/6 inhibitors might stimulate anti-tumor immune responses, focusing on breast cancer. I will also discuss if and how this unexpected phenomenon might be leveraged for therapeutic benefit.

Citation Format: Goel S. Modulation of anti-tumor immunity using CDK4/6 inhibitors [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 TS3-2.
Abstract A06: Novel NF-kB reporter murine model of spontaneous, metastatic breast cancer for spatiotemporal monitoring of local and systemic therapeutic response
Authors: Dockery Mary , Poorman Megan , Dudzinski Stephanie , Barham Whitney , Chaplin Vandiver , Spears Ryan , Kusunose Jiro , Yull Fiona , Caskey Charles , Grissom William , Giorgio Todd
Published: May 2019

Characterization of therapeutic response in primary and metastatic tumors is limited by endpoint studies and tissue collection. We have successfully developed a unique double-transgenic mouse model, which combines the polyoma virus middle T oncogene (PyVT), a model of human breast cancer, with a nuclear factor-kappaB (NF-kB) reporter model (NGL). PyVT mice spontaneously form primary mammary fat pad tumors, with 80% of mice developing metastatic lesions in the lungs. The reporter is luciferase, driven by NF-kB activation, to provide quantitative bioluminescent measurements of spatially-specific NF-kB activity. The resulting double transgenic (PyNGL) mice were monitored using in vivo imaging systems (IVIS) multiple times, before and after treatment, to quantitatively and spatially characterize NF-kB therapeutic response, both locally and systemically.

High intensity focused ultrasound (HIFU) was guided by magnetic resonance (MR) thermometry for tumor-localized hyperthermia which was dosage-controlled by the thermal feedback MR guided HIFU (MRgHIFU) system. A single primary mammary tumor in each PyNGL was treated with sub-ablative hyperthermia of 42⁰ for up to 25 minutes. Pre-treatment IVIS measurements were collected to determine baseline NF-kB activity within each mouse, followed by IVIS imaging every twelve hours after treatment until tissue collection. Treated tumor, contralateral (untreated) tumors, and spleens were collected for immunophenotyping and cytokine analysis using flow cytometry. PyNGL mice exhibited decreased NF-kB activity, spatially correlated with HIFU treatment, as early as 12 hours. In contrast, NF-kB increased in contralateral tumors as early as 24 hours following treatment. Immunophenotyping reveals changes in tumor infiltrating leukocyte populations in HIFU-treated and contralateral tumors, including quantity and phenotype of T cells.

The unique murine model developed allowed quantitative, temporal characterization of local and distant tumor response to MFgHIFU. The spontaneous, metastatic nature of PyVT tumor formation in concert with the non-destructive, spatiotemporal imaging capabilities of the NF-kB reporter transgene make the PyNGL model an unparalleled tool for research in metastatic disease.

Citation Format: Mary Dockery, Megan Poorman, Stephanie Dudzinski, Whitney Barham, Vandiver Chaplin, Ryan Spears, Jiro Kusunose, Fiona Yull, Charles Caskey, William Grissom, Todd Giorgio. Novel NF-kB reporter murine model of spontaneous, metastatic breast cancer for spatiotemporal monitoring of local and systemic therapeutic response. [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 A06.
Abstract A17: TRPM7 kinase domain is involved in breast tumor cell metastasis
Authors: Kaoud Tamer S. , Xie Xuemei , Park Jihyun , Tavares Clint D.J. , Mitra Shreya , Cano Micael , Radwan Mohamed F. , Bartholomeusz Chandra , Dalby Kevin N.
Published: May 2019

Introduction: TRPM7 (transient receptor potential melastatin 7) is a non-selective cation channel fused to protein kinase domain at the C-terminal whose activity is linked to the control of actomyosin contractility. TRPM7 mediates adhesion and migration of breast cancer cells and promotes breast tumor metastasis. The lack of cell-permeable inhibitors of the kinase domain represents a barrier to understand the kinase function.

Methods: Herein, we discover the first small molecule (KD-1) that targets TRPM7 kinase activity and characterize its mechanism of action in-vitro, in-cells and in-vivo. By using this inhibitor, we are investigated the involvement of TRPM7 kinase domain in breast tumor cell metastasis.

Results: Mg2+ starvation, which promotes TRPM7 kinase activity, induces phosphorylation of eEF2. Treatment of Mg2+-starved HEK293 cells with KD-1 decreased eEF2 phosphorylation, consistent with TRPM7 kinase activity suppression in-cells. KD-1 decreased the binding of Myosin IIB to TRPM7 in HEK293 and MDA-MB-231 cells. And when MDA-MB-231 and BT 549 cells were treated with increasing doses of KD-1, no change in cell viability was seen. Interestingly, KD-1 inhibited migration and invasion in the MDA-MB-231 and BT 549 cells that is reportedly regulated by TRPM7 kinase activity. Finally, the bioluminescent signals (to assess lung metastasis) were significantly lower in KD-1-treated mice (25 and 50 mg/kg/day) than in mice treated with vehicle control (P ≤0.05, 2-sided t-test.).

Conclusion: The discovered compound represents the first inhibitor that targets the kinase activity of transient receptor potential melastatin 7 (TRPM7). Inhibition of TRPM7 kinase activity may reduce or block breast tumor progression and/or metastasis.

Citation Format: Tamer S. Kaoud, Xuemei Xie, Jihyun Park, Clint D.J. Tavares, Shreya Mitra, Micael Cano, Mohamed F. Radwan, Chandra Bartholomeusz, Kevin N. Dalby. TRPM7 kinase domain is involved in breast tumor cell 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 A17.
Abstract A18: Development of a novel peptide therapeutic that targets ovarian cancer via the tumor microenvironment
Authors: Wang Suming , Blois Anna , Rayes Tina EI , Liu Joyce F. , Hirsch Michelle S. , Gravdal Karsten , Bielenberg Diane R. , Akslen Lars A. , Drapkin Ronny , Mittal Vivek , Watnick Randolph S.
Published: May 2019

Ovarian cancer is the most lethal gynecologic malignancy and the fourth leading cause of cancer deaths in women. Pathologically, ovarian cancer is categorized into multiple subtypes, with epithelial ovarian cancer (EOC) representing 90% of cases. Despite our increased understanding of the biology governing the progression of EOC the survival rate for patients with stage IV EOC is only 17%. The vast majority of ovarian cancer-related deaths are caused by metastatic dissemination of cells from the primary tumor resulting in subsequent organ failure. Tragically, there are no clinically approved drugs that have shown significant efficacy at treating advanced, metastatic, ovarian cancer. As such, there is a dire need for efficacious therapies that can specifically treat advanced, metastatic ovarian cancer. We were the first to identify prosaposin (psap) as a potent inhibitor of tumor metastasis via stimulation of the anti-tumorigenic protein thrombospondin-1 (Tsp-1) in bone marrow-derived cells that are recruited to metastatic sites. We report here that virtually 100% of human serous ovarian tumors tested express CD36, the receptor that mediates the pro-apoptotic activity of Tsp-1. Accordingly, we developed a novel cyclic peptide with drug-like properties derived from the active sequence in psap. Strikingly, this cyclic psap peptide was able to significantly regress metastatic tumors in a patient-derived tumor xenograft (PDX) model of metastatic ovarian cancer. Thus, our findings suggest that development of a therapeutic agent based on this psap peptide would have significant efficacy in treating patients with metastatic ovarian cancer.

Citation Format: Suming Wang, Anna Blois, Tina EI Rayes, Joyce F. Liu, Michelle S. Hirsch, Karsten Gravdal, Diane R. Bielenberg, Lars A. Akslen, Ronny Drapkin, Vivek Mittal, Randolph S. Watnick. Development of a novel peptide therapeutic that targets ovarian cancer via the tumor microenvironment. [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 A18.
Abstract A21: Hypoxia preconditioning affects metastatic seeding and proliferation through vascular and immune function, in a process regulated by lung endothelial HIFa
Authors: Branco Cristina , Rundqvist Helene , Colaco Renato , Johnson Randall S.
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 (PR03) of the Conference Proceedings.

Citation Format: Cristina Branco, Helene Rundqvist, Renato Colaco, Randall S. Johnson. Hypoxia preconditioning affects metastatic seeding and proliferation through vascular and immune function, in a process regulated by lung endothelial HIFa. [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 A21.
Abstract A30: The role of neutrophil extracellular traps in promoting metastatic cancer following surgical stress
Authors: Tohme Samer , Huang Hai , Chidi Alexis , Simmons Richard , Tsung Allan
Published: May 2019

Background: Surgical removal of malignancies may enhance the risk of recurrence but mechanisms remain poorly understood. Neutrophils, first line responders after surgical stress, can facilitate cancer progression. Neutrophils can expel nuclear DNA studded with proteins to form web-like structures known as Neutrophil Extracellular Traps (NETs) in response to stress. Here we aim to characterize the role of NETs in promoting metastatic cancer growth after surgical stress that is currently entirely unknown.

Methods: We used a standardized mouse model of partial hepatic ischemia reperfusion, to stimulate surgical stress, directly or five days after splenic injection of MC38 colon carcinoma cells.

Results: We found that NET formation is significantly increased in the immediate post-operative period in humans undergoing curative liver resection for colorectal cancer metastases. The risk of liver metastases recurrence was 4.22 times higher in patients with increased post-operative NET formation. In the murine model, we demonstrated increased NET deposition after surgical stress and this was associated with both increased formation of metastases and growth of already established micrometastatic disease. In vitro, NETs increase growth, invasion, migration and adhesion in multiple cancer cell lines. All the above effects were abrogated by NET inhibition with DNAse. NETs exert their pro-tumorigenic effects by releasing HMGB1 and activating TLR-9 dependent pathways in the cancer cells. In addition, as metastatic tumors continue to grow, hypoxia within the tumor microenvironment induces further neutrophil recruitment and NET formation that further accelerates tumor growth.

Conclusions: These findings implicate NETs in the process of cancer metastasis progression and recurrence after surgery and identifies NETs as potential therapeutic targets.

Citation Format: Samer Tohme, Hai Huang, Alexis Chidi, Richard Simmons, Allan Tsung. The role of neutrophil extracellular traps in promoting metastatic cancer following surgical stress. [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 A30.
Abstract A33: The regulation of extracellular acidosis and cell survival by the TIMP-1/CD63 axis in breast carcinoma
Authors: Najy Abdo J. , Jung Young Suk , Kim Hyeong-Reh Choi
Published: May 2019

Breast Cancer (BrCa) resistance to conventional therapies often leads to more aggressive and metastatic disease highlighting the importance of understanding the resistance pathway. The Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) is among the most reliable prognostic markers for therapy resistance as well as metastasis of breast cancer via promotion of breast cancer cell survival through its unique interaction with the tetraspanin CD63. Recent work has shown that levels of TIMP-1 and the carbonic anhydrase family member CAIX in circulating tumor cells (CTCs) predict BrCa progression-free and overall survival. Since CAIX is known to play a critical role in the regulation of extracellular acidosis that contributes to therapy resistance, we investigated whether TIMP-1/CD63 signaling regulates extracellular acidosis involving CAIX. We utilized the murine 4T1 and human MCF10A progression models of breast cancer and demonstrated increased CAIX and TIMP-1 expression in the more aggressive 4T1 and MCF10CA1h cells. When we monitored pH change using a digital pH reader and the pH sensitive DF fluorescein dye, the more aggressive human MCF10Ca1h cells exhibited marked extracellular acidosis compared to the minimally malignant MCF10A and MCF10AneoT cells. Importantly, downregulation of TIMP-1 or CD63 in MCF10CA1h cells specifically reduced CAIX expression and its associated extracellular acidosis. To determine the functional significance of CAIX in TIMP-1/CD63-mediated extracellular acidosis, we attenuated CAIX expression and demonstrated a significant reduction of the acidosis phenotype observed in MCF10CA1h cells. Importantly, CAIX knockdown drastically reduced BrCa cell survival in a clonogenic cell survival assay. Taken together, we have identified a unique TIMP-1/CD63-mediated signaling pathway, resulting in extracellular acidosis and cell survival of BrCa cells involving CAIX. This study further provides salient information as to TIMP-1-specific function in breast cancer.

Citation Format: Abdo J. Najy, Young Suk Jung, Hyeong-Reh Choi Kim. The regulation of extracellular acidosis and cell survival by the TIMP-1/CD63 axis in breast carcinoma. [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 A33.
Abstract A47: A patient-derived xenograft model of pancreatic cancer in mice to develop novel adjuvant therapies
Authors: Mullen Matthew G. , Newhook Timothy E. , Lindberg James M. , Adair Sara J. , Blais Edik M. , Michaels Alex D. , Stelow Edward B. , Papin Jason A. , Parsons J. Thomas , Bauer Todd W.
Published: May 2019

Background: Eighty percent of patients with pancreatic ductal adenocarcinoma (PDAC) die from their disease within five years of surgical resection, likely due to presence of occult metastases at diagnosis. We have developed a patient-derived xenograft (PDX) model in mice to investigate the behavior of occult metastatic cells in the liver microenvironment and derive novel adjuvant therapies.

Methods: Five PDAC tumors (215, 366, 608, 654 and 738) were resected from patients and implanted orthotopically in mice. Tumors were harvested, cell lines generated and transduced with luciferase, then injected into spleens of mice to generate microscopic liver metastases, then primary tumors removed via splenectomy. Bioluminescence imaging of mice and histologic analysis and flow cytometry of livers were utilized to characterize each tumor's distinct pattern of cell clearance and outgrowth kinetics. Affymetrix gene expression of tumors was performed. Mice were treated with adjuvant therapy following resection of primary tumors in the spleen and time-to-progression (TTP) and overall survival (OS) were measured.

Results: Each PDX cell line demonstrated unique and reproducible clearance in the liver and outgrowth kinetics as measured by bioluminescence imaging. Distinct differences in gene expression were identified in tumors exhibiting rapid vs. delayed outgrowth. The MEK inhibitor trametinib (0.3 mg/kg oral daily) prolonged TTP and OS vs. control (OS - Tumor 608: 114 vs. 43 days, p<0.001; Tumor 366: MS not achieved vs. 167 days, p=0.0488). In a randomized preclinical trial, sequential therapy with gemcitabine followed by trametinib provided a survival advantage and increased TTP when compared with control and single agent gemcitabine treatment.

Conclusions: This PDX PDAC model of occult metastasis allows characterization of hepatic clearance of tumor cells and outgrowth kinetics. Metastatic outgrowth appears to be dependent upon distinguishable tumor cell-specific factors. Trametinib effectively inhibits KRAS-MEK-ERK signaling, delays outgrowth of occult metastases and prolongs survival of mice. Utilization of this model will help further define the complex interaction of PDAC cells and the metastatic microenvironment of the liver.

Citation Format: Matthew G. Mullen, Timothy E. Newhook, James M. Lindberg, Sara J. Adair, Edik M. Blais, Alex D. Michaels, Edward B. Stelow, Jason A. Papin, J. Thomas Parsons, Todd W. Bauer. A patient-derived xenograft model of pancreatic cancer in mice to develop novel adjuvant therapies. [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 A47.
Abstract A66: Systemic effects of AC-T chemotherapy in breast cancer
Authors: DeCristo Molly J. , McAllister Sandra S.
Published: May 2019

Cytotoxic chemotherapy is the only standard of care treatment currently available for patients with triple negative breast cancer (TNBC) because this breast cancer subtype lacks expression of therapeutic targets, namely, estrogen receptor, progesterone receptor, and amplification of Her2. Despite the efficacy of neoadjuvant chemotherapy for some TNBC patients, approximately 60-80% of TNBC patients will still present with local and distant disease after therapy, and these patients suffer poor prognosis. In addition to direct effects on tumor cells, systemic chemotherapy also has the potential to impact patient physiology. However, the implications of tumor-cell independent effects of chemotherapy for metastatic progression are not well understood. We are using mouse models of TNBC to study the effects of chemotherapy on host physiology and how these effects impact metastasis. Treatment of TNBC tumor-bearing mice with doxorubicin (A), cyclophosphamide (C), and paclitaxel (T) decreased overall bone marrow cell counts; although, the degree of decrease and subsequent recovery of individual bone marrow and circulating cell populations varied among populations. Notably, parallel experiments in tumor-free mice demonstrated that chemotherapy-dependent effects on the bone marrow and circulating cell populations dominate tumor-dependent effects. These findings highlight the potential implications of the physiological effects of chemotherapy on metastasis and response to therapy.

Citation Format: Molly J. DeCristo, Sandra S. McAllister. Systemic effects of AC-T chemotherapy 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 A66.
Abstract A67: Elucidating the impact of zoledronic acid on the bone microenvironment: Implications for breast cancer
Authors: Ubellacker Jessalyn M. , McAllister Sandra S.
Published: May 2019

Bisphosphonates, such as zoledronic acid (ZOL), are bone microenvironment modulators that work primarily by inhibiting the activity of bone resorbing osteoclasts and have demonstrated ability to reduce breast cancer risk and recurrence in the bone in clinical trials. Previous work in our laboratory has demonstrated the ability of tumor-derived factors (osteopontin) to activate pro-tumorigenic bone marrow hematopoietic cells, which subsequently promote tumor outgrowth. The aim of this current study is to determine whether ZOL inhibits the impact of such tumor-derived paracrine factors on the bone microenvironment, thus reducing metastatic outgrowth in the bone. A human bone-tropic breast cancer cell line (MDA-MB-231 BO2) was introduced into NU/J mice via intracardiac (IC) and intratibial (IT) injections 72 hours after treating the mice with ZOL. Cell seeding was assessed at 24 hours by CM-DiL staining, and subsequent tumor outgrowth was monitored weekly by bioluminescence. One ZOL pre-dose was sufficient to decrease both tumor cell seeding (via IC) and colonization (via IT) relative to the robust tumor outgrowth observed in mice treated with vehicle control. Additionally, subcutaneous ad-mixtures of MDA-MB-231 BO2 cells with bone marrow cells from ZOL-treated mice demonstrated a decreased incidence of tumor formation relative to control bone marrow cells, indicating that the tumor inhibitory effect of ZOL occurs via modulations to the bone marrow hematopoietic microenvironment. A second MDA-MB-231 bone-tropic cell line similar to the BO2 line, but with higher expression levels of CXCL1, G-CSF, GM-CSF and IL8, was not inhibited by ZOL in the IC and IT bone metastasis models. These results implicate the role of certain tumor-derived paracrine factors in mediating resistance to ZOL treatment. These findings are important for elucidating the therapeutic potential of bisphosphonates for treating at-risk patients in the adjuvant setting before they develop incurable metastatic disease.

Citation Format: Jessalyn M. Ubellacker, Sandra S. McAllister. Elucidating the impact of zoledronic acid on the bone microenvironment: Implications for 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 A67.
Abstract B02: Silencing of semaphorin 7a attenuates breast tumor progression
Authors: Black Sarah , Nelson Andrew , Gurule Natalia , Futscher Bernard , Lyons Traci
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 (PR10) of the Conference Proceedings.

Citation Format: Sarah Black, Andrew Nelson, Natalia Gurule, Bernard Futscher, Traci Lyons. Silencing of semaphorin 7a attenuates breast tumor progression. [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 B02.
Abstract B26: Epigenetic master regulator EPC1 is a decisive factor for E2F1 to silence cell death and activate metastatic gene signatures in response to DNA damage
Authors: Engelmann David , Wang Yajie , Alla Vijay , Goody Deborah , Gupta Shailendra K. , Spitschak Alf , Pützer Brigitte M.
Published: May 2019

The transcription factor E2F1 is a key regulator of cell proliferation and apoptosis. Recently, it has been shown that aberrant E2F1 expression often detectable in advanced-stage metastatic and chemoresistant cancers contributes essentially to malignant progression and characterizes the aggressive potential of a tumor. Conceptually, this requires a subset of malignant cells capable of evading apoptotic death through anticancer drugs. The molecular mechanism by which the pro-apoptotic activity of E2F1 is antagonized is widely unclear. Here we report a novel function for enhancer of polycomb homolog 1 (EPC1) in DNA damage protection. Depletion of EPC1 potentiates E2F1-mediated apoptosis in response to genotoxic treatment and abolishes tumor cell motility. We found that E2F1 directly binds and activates the EPC1 promoter and EPC1 vice versa physically interacts with bifunctional E2F1 to modulate its transcriptional activity in a target gene-specific manner. Remarkably, nuclear-colocalized EPC1 activates E2F1 to upregulate the expression of anti-apoptotic survival genes such as BCL-2 or Survivin and inhibits death-inducing targets including p27 and Bim. Mechanistically, we observed that EPC1 is required for recruitment of Tip60, a subunit of the NuA4 acetyltransferase complex, to E2F sites of the Bcl-2 promoter, causing increased activating histone acetylation levels. In contrast, ablation of EPC1 removes the PRC2 component EZH2 from the p27 promoter, resulting in decreased histone methylation for E2F1-mediated gene activation. In this scenario, EPC1 acts as a crucial bridging factor to connect E2F1 with essential components of the chromatin remodeling complexes Nu4A and PRC2. The uncovered cooperativity between EPC1 and E2F1 triggers a gene signature in advanced cancers that predicts metastatic behavior and poor patient survival. These findings unveil a novel oncogenic function of EPC1 for inducing the switch into tumor progression-relevant gene expression that may help to set novel therapies.

This work was supported by German Cancer Aid, Dr. Mildred Scheel Stiftung (109801 to B.M.P. and D.E.) and German Federal Ministry of Education and Research (BMBF) as part of the eBio:SysMet project (0316171 to B.M.P.).

Note: This abstract was not presented at the conference.

Citation Format: David Engelmann, Yajie Wang, Vijay Alla, Deborah Goody, Shailendra K. Gupta, Alf Spitschak, Brigitte M. Pützer. Epigenetic master regulator EPC1 is a decisive factor for E2F1 to silence cell death and activate metastatic gene signatures in response to DNA damage. [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 B26.