Efficacy In Breast Cancer Research Articles

Pulmonary metastasectomy for pulmonary metastasis of breast cancer has a limited prognostic impact: a multi-institutional retrospective analysis.

BackgroundPulmonary metastasectomy (PM) for breast cancer-derived pulmonary metastasis is controversial. This study aimed to assess the prognostic factors and implication of PM for metastatic breast cancer using a multi-institutional database.MethodsClinical data of 253 females with pulmonary metastasis of breast cancer who underwent PM between 1982 and 2017 were analyzed retrospectively.ResultsThe median patient age was 56 years. The median follow-up period was 5.4 years, and the median disease-free interval (DFI) was 4.8 years. The 5- and 10-year survival rates after PM were 64.9% and 50.4%, respectively, and the median overall survival was 10.1 years. Univariate analysis revealed that the period of PM before 2000, a DFI <36 months, lobectomy/pneumonectomy, large tumor size, and lymph node metastasis were predictive of a worse overall survival. In the multivariate analysis, a DFI <36 months, large tumor size, and lymph node metastasis remained significantly related to overall survival. The 5- and 10-year cancer-specific survival rates after PM were 66.9% and 54.7%, respectively, and the median cancer-specific survival was 13.1 years. Univariate analyses revealed that the period of PM before 2000, DFI <36 months, lobectomy/pneumonectomy, large tumor size, lymph node metastasis, and incomplete resection were predictive of a worse cancer-specific survival. Multivariate analysis confirmed that a DFI <36 months, large tumor size and incomplete resection were significantly related to cancer-specific survival.ConclusionsAs PM has limited efficacy in breast cancer, it should be considered an optional treatment for pulmonary metastasis of breast cancer.

MiR-520b Inhibits IGF-1R to Increase Doxorubicin Sensitivity and Promote Cell Apoptosis in Breast Cancer.

Doxorubicin (DOX) is currently one of the most widely used and effective drugs for the treatment of breast cancer, but drug resistance in breast cancer often leads to poor efficacy. MicroRNAs (miRNAs) are involved in the development and progression of various tumors and increasing number of studies have confirmed that abnormal miR-520b expression is closely associated breast cancer. We analyzed the clinical features, including miR-520b, of 30 patients with breast cancer. Further, we analyzed the interaction between miR-520b and insulin-like growth factor 1 receptor (IGF-1R) in breast cancer cell. miR-520b expression was significantly increased in chemotherapy-sensitive patients and was positively correlated with the chemotherapeutic efficacy in breast cancer. Cell proliferation assay confirmed that miR-520b promotes DOX-induced breast cancer cell apoptosis by regulating the PI3K/AKT signaling pathway. Moreover, bioinformatics method and dual luciferase reporter assay demonstrated that miR-520b negatively regulates IGF-1R, and IGF-1R overexpression and enhanced activity are closely associated with tumor development, progression, metastasis, and chemotherapy resistance. Similarly, cell proliferation assay showed that IGF-1R is negatively correlated with the efficacy of DOX chemotherapy and affects cell apoptosis mediated by the PI3K/AKT signaling pathway. On the contrary, miR-520b can downregulate the expression of IGF-1R. miR-520b increases DOX sensitivity and promotes cell apoptosis in breast cancer by inhibiting IGF-1R expression by the PI3K/AKT signaling pathway.

Combined LIM kinase 1 and p21-Activated kinase 4 inhibitor treatment exhibits potent preclinical antitumor efficacy in breast cancer.

LIM kinase 1 (LIMK1) and p21-activated kinase 4 (PAK4) are often over-expressed in breast tumors, which causes aggressive cancer phenotypes and unfavorable clinical outcomes. In addition to the well-defined role in regulating cell division, proliferation and invasion, the two kinases promote activation of the MAPK pathway and cause endocrine resistance through phosphorylating estrogen receptor alpha (ERα). PAK4 specifically phosphorylates LIMK1 and its functional partners, indicating possible value of suppressing both kinases in cancers that over-express PAK4 and/or LIMK1. Here, for the first time, we assessed the impact of combining LIMK1 inhibitor LIMKi 3 and PAK4 inhibitor PF-3758309 in preclinical breast cancer models. LIMK1 and PAK4 pharmacological inhibition synergistically reduced the survival of various cancer cell lines, exhibiting specific efficacy in luminal and HER2-enriched models, and suppressed development and ERα-driven signals in a BT474 xenograft model. In silico analysis demonstrated the cell lines with reliance on LIMK1 were the most prone to be susceptible to PAK4 inhibition. Double LIMK1 and PAK4 targeting therapy can be a successful therapeutic strategy for breast cancer, with a unique efficiency in the subtypes of luminal and HER2-enriched tumors.

Regulation of immune checkpoint blockade efficacy in breast cancer by FIP200: A canonical-autophagy-independent function.

Immune checkpoint blockade (ICB) has emerged as a promising therapeutic strategy because of its potential to induce durable therapeutic responses in cancer patients. However, in the case of breast cancer, its application and efficacy has been limited. As such, combinatorial therapeutic strategies that can unlock the potential of ICB in breast cancer are of urgent need. In view of that, autophagy-related proteins that play a role in the autophagic cell recycling process have been implicated in the regulation of inflammatory and anti-tumor immune responses. Accordingly, autophagy-related proteins represent a group of prospective therapeutic targets in conjunction with ICB. In our recent study (Okamoto T et al. (2020), Cancer Res), we developed immune-competent mouse models of breast cancer which were deficient for the autophagic function of FIP200 or had FIP200 completely ablated to test the efficacy of ICB. We showed that although FIP200's autophagy function was required for progression of PyMT-driven mammary tumors, FIP200's canonical-autophagy-independent function was responsible for increased T-cell infiltration, IFN-signaling and ICB efficacy. These findings provide genetic proof of principle for a combinatorial therapeutic strategy that involves ablation of FIP200 to improve ICB efficacy in non-responsive breast cancers.

54. tGLI1 IS AN ACTIONABLE THERAPEUTIC TARGET IN BREAST CANCER BRAIN METASTASES

Breast cancer is the second leading cause of brain metastases in women; patients with breast cancer brain metastasis (BCBM) survive an average of 6–18 months following diagnosis. Cancer stem cells are thought to be one of the driving forces behind distant metastasis, treatment resistance, and late-stage recurrence. The hedgehog-smoothened pathway has been identified as an important mediator of breast cancer stem cells (BCSC); however, FDA-approved therapies targeting smoothened have demonstrated limited clinical efficacy in breast cancer. Despite advances made in understanding BCSC, it is still challenging to effectively target BCSC underscoring the need to identify and inhibit novel mediators of BCSC for treating BCBM patients. Our laboratory recently reported that truncated glioma-associated oncogene homolog 1 (tGLI1) promotes preferential metastasis to the brain in breast cancer by activating BCSC and astrocytes in the tumor microenvironment (Oncogene 39:64–78, 2020). tGLI1 was discovered in our laboratory as an alternatively spliced GLI1 that functions as a tumor-specific gain-of-function transcription factor and terminal effector of the hedgehog pathway. We found that tGLI1 knockdown abrogated BCBM, providing the rationale to therapeutically target tGLI1. Cell-based chemical screens followed by validations demonstrated that ketoconazole, an FDA-approved azole antifungal, specifically inhibits tGLI1 leading to suppression of BCSC in vitro and BCBM in vivo. Based on these data, we opened a window-of-opportunity study in patients with BCBM to determine if ketoconazole penetrates the blood-brain barrier (BBB) and alters tGLI1 signaling in humans (NCT03796273). Preliminary sample analysis has confirmed tGLI1 expression in collected BCBM samples. To help identify more effective tGLI1 inhibitors, we screened 63 azole compounds for tGLI1-selectivity and identified four additional compounds as potential tGLI1 inhibitors. Animal studies were performed to compare the efficacy of these four compounds with ketoconazole in suppressing BCBM. Collectively, these data establish tGLI1 as an actionable target for BCBM.

Nanoformulated Ajwa (Phoenix Dactylifera) Bioactive Compounds Improve the Safety of Doxorubicin without Compromising its Anticancer Efficacy in Breast Cancer.

One of the major causes of women’s death in the world is breast cancer. Consequently, numerous regimens for the control of this severe disease have been created. The chemotherapeutic agent doxorubicin (DOX) is frequently used to treat breast cancer, but DOX can also cause cardiotoxic effects that lead to heart failure. Therefore, many research studies have been done to find a natural product that effectively potentiates or does not interfere with DOX’s anticancer effect and protects against its cardiotoxicity. We studied the impact of combined nanoformulated Ajwa (Phoenix dactylifera) selected bioactive compounds (BAC) rutin (R) and quercetin (Q) in nude mice breast cancer xenografts on DOX-mediated anticancer efficacy. We also studied if this Ajwa BAC could safeguard against DOX-mediated cardiomyopathies by evaluating plasma cardiac troponin-I (cTn-I) levels and cardiac histopathology. Nanoformulated Ajwa BAC effectively alleviated weight loss induced by DOX in mice and significantly decreased the elevated cTn-I. Furthermore, 5 mg RQ-NPs/kg of nude mice that subcutaneously daily injected for 11 days, attenuated the histopathological alterations induced in cardiac muscles due to DOX without any interference with the anticancer effects of DOX against breast cancer.

Rlip Depletion Suppresses Growth of Breast Cancer

RLIP76 (RAL-binding protein-1, Rlip) is a stress-protective mercapturic-acid-pathway transporter protein that also plays a key role in regulating clathrin-dependent endocytosis as a Ral effector. Targeted inhibition or depletion of Rlip causes regression of xenografts of many cancers and is capable of abrogating tumor formation in p53-null mice. This is associated with the reversion of the abnormal methylomic profile of p53-null mice to wild-type. In a query of The Cancer Genome Atlas (TCGA) databases, we found that Rlip expression was associated with poor survival and with significant differences in the frequencies of PIK3CA mutation, MYC amplification, and CDKN2A/B deletion, which were the most commonly mutated, amplified, and deleted genes, respectively, among TCGA breast cancer patients. We conducted the present study to further examine the effects of Rlip inhibition and to evaluate the in vitro and in vivo efficacy in breast cancer. Using immunogold electron microscopy, we found that plasma-membrane Rlip was accessible to cell-surface antibodies in the MCF7 (ER+) breast cancer cell line. Rlip depletion resulted in decreased survival of MCF7 and MDA-MB-231 cells and increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity and DNA laddering, indicating apoptotic cell death. Additionally, in vitro knockdown of Rlip inhibited EGF endocytosis and WNT/MAPK signaling. Xenograft studies in nude mice showed regression of breast cancer via antisense-mediated depletion of Rlip mRNA as well as by anti-Rlip antibody. Finally, knockdown of Rlip by antisense locked nucleic acid oligonucleotides increased markers for apoptotic signaling and decreased markers for proliferation, angiogenesis, and cell cycling in MCF7 and MDA-MB-231luc xenografts. Our findings validate Rlip as an attractive target in breast cancer.

Abstract B020: Antiproliferative efficacy of different targeted drugs on breast cancer cell lines of distinct subtypes

Abstract Background: Breast cancer is the most common cancer overall, with an estimated 2.4 million incident cases in 2015. Current treatment of breast cancer is mainly surgery, chemotherapy, radiotherapy, and hormonal therapy. Although these approaches appear to be effective, they have failed to result in long-term cure, especially for aggressive HER2-positive and triple-negative breast cancer. This particularly holds for sub-Saharan Africa with a dominance of aggressive breast cancer subtypes with very limited treatment options and almost no research activities in place. As a result, continuous exploration of alternative treatment strategies is urgently required. Consequently, a collaborative research program has been established between Addis Ababa University, Ethiopia, and Martin-Luther-University, Germany, to enhance breast cancer research in Ethiopia. As a pilot study in Germany, we have assessed the in vitro potency of the three inhibitors romidepsin, trametinib, and lapatinib targeting HDAC, MEK and HER2/EGFR, respectively, in different breast cancer cell lines. Methods: Seven distinct breast cancer cell lines (MCF7, SKBR3, T47D, BT474, BT20, HCC1806 and HCC1937) of known HER-2 and hormone status were used to evaluate the antiproliferative effect of romidepsin, lapatinib, and trametinib. Cells cultivated in complete RPMI media were seeded in to 96 well plates (3,000 cells/well) and incubated at 370C and 5% CO2 for 24hrs. The cells were then treated for 24, 48, and 72 hours with different concentrations of the drugs. Cells exposed to solvent alone served as controls. XTT cell viability assay was used to determine proliferation of cells following manufacturers' instruction. IC50 value was calculated (Compusyn software) for each drug against the different cell lines to determine the antiproliferative effect. Results: Romidepsin exhibited a strong antiproliferative effect against all breast cancer cell lines tested, resulting in a marked decrease in cell viability with increasing concentrations, which highly varied between the breast cancer cell lines analyzed. The calculated IC50 values 48 hrs after the onset of treatment ranged between 2.2 and 52 nM; T47D was the most sensitive. Lapatinib treatment of the EGFR/HER-2 expressing BT20, SKBR3 and BT474 caused dose-dependent suppression of cell viability against SKBR3 and BT474 with an IC50 value of 450 and 77 nM, respectively. In contrast, BT20 cells were resistant to this treatment and were the only breast cancer cell line with an enhanced sensitivity to increasing concentrations of trametinib (IC50 =2.79 μM). Conclusion: In sum, romidepsin might improve the treatment efficacy of breast cancer though it needs to be further explored in vitro as well as in vivo alone and in combination with other therapies. Although trametinib has been suggested to be insufficient for monotherapy of breast cancer in general, it might be still a candidate for the treatment of basal-like breast cancers due to the sensitivity of BT20 cells. Citation Format: Meron Yohannes Nigussie, Jürgen Bukur, Zelalem Desalegn Woldesonbet, Tamrat Abebe Zeleke, Yonas Bekuretsion, Mahlet Arayselassie, Mathewos Assefa, Abebe Bekele, Endale Anberber, Martina Vetter, Claudia Wickenhauser, Eva J Kantelhardt, Barbara Seliger. Antiproliferative efficacy of different targeted drugs on breast cancer cell lines of distinct subtypes [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B020.

CD103+ cDC1 vaccine efficacy in murine breast cancer is inhibited by STAT3

Abstract Conventional dendritic cells (cDCs) are a crucial immune population, which includes multiple subtypes that coordinate adaptive immunity and tolerance. Migratory type 1 cDC1s (CD103+ cDC1s in mice) are required to induce CD8+ T cell-mediated anti-tumor immunity, yet whether and how tumors regulate CD103+ cDC1 function is largely unknown. Many tumor-associated immunosuppressive cytokines, such as interleukin (IL)-10, require Signal Transducer and Activator of Transcription 3 (STAT3) for intracellular signaling; therefore, we sought to determine whether STAT3 inhibits CD103+ cDC1-mediated anti-tumor immunity. Indeed, we found that in vitro-derived STAT3-deficient (Stat3Δ/Δ) CD103+ cDC1sare resistant to IL-10 – mediated inhibition of Toll-like receptor 3 (TLR3)-agonist induced maturation. When used as an anti-tumor vaccine, Stat3Δ/Δ CD103+ cDC1s inhibited breast tumor growth and increased mouse survival to a greater degree than STAT3-sufficient CD103+ cDC1s. Vaccination with Stat3Δ/Δ CD103+ cDC1s increased tumor antigen-specific CD8+ T cells and IFN-g+ CD4+ T cells in tumors and tumor-draining lymph nodes compared to controls. Moreover, IL-10 receptor-deficient CD103+ cDC1s restrained tumor growth as effectively as Stat3Δ/Δ CD103+ cDC1s. Taken together, our results demonstrate STAT3 suppresses CD103+ cDC1 maturation and vaccine efficacy in breast cancer. The data also suggest IL-10 is an important factor in the murine mammary tumor environment mediating immunosuppressive STAT3 signaling in CD103+ cDC1s. Thus, STAT3 inhibition may provide an effective strategy for improving the anti-tumor efficacy of CD103+ cDC1-based vaccines.

Hypoxia Attenuates Trastuzumab Uptake and Trastuzumab-Emtansine (T-DM1) Cytotoxicity through Redistribution of Phosphorylated Caveolin-1.

The antibody-drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of T-DM1 and its metabolites was evaluated in conjunction with biochemical, flow cytometry, and high-resolution imaging studies to elucidate the functional and mechanistic aspects of hypoxic regulation. HER2 and caveolin-1 expression was investigated in a well-annotated breast cancer cohort. We find that hypoxia fosters relative resistance to T-DM1 in HER2+ cells (SKBR3 and BT474). This effect was not a result of deregulated HER2 expression or resistance to emtansine and its metabolites. Instead, we show that hypoxia-induced translocation of caveolin-1 from cytoplasmic vesicles to the plasma membrane contributes to deficient trastuzumab internalization and T-DM1 chemosensitivity. Caveolin-1 depletion mimicked the hypoxic situation, indicating that vesicular caveolin-1 is indispensable for trastuzumab uptake and T-DM1 cytotoxicity. In vitro studies suggested that HER2 and caveolin-1 are not coregulated, which was supported by IHC analysis in patient tumors. We find that phosphorylation-deficient caveolin-1 inhibits trastuzumab internalization and T-DM1 cytotoxicity, suggesting a specific role for caveolin-1 phosphorylation in HER2 trafficking. IMPLICATIONS: Together, our data for the first time identify hypoxic regulation of caveolin-1 as a resistance mechanism to T-DM1 with potential implications for individualized treatment of breast cancer.

Cancer therapy in good order

Cancer Treatment of cancer patients with two or more drugs acting through different mechanisms is a strategy that has prolonged many lives. Whether the drugs within these combination therapies are delivered concurrently or sequentially can have a major impact on efficacy. A new study illustrates this principle for drugs that inhibit cell cycle kinases CDK4 and CDK6 (CDK4/6 inhibitors), which have attracted great interest because of their clinical efficacy in breast cancer. Studying mouse models of pancreatic cancer, Salvador-Barbero et al. found that sequential treatment with Taxol (which inhibits mitosis) followed by a CDK4/6 inhibitor (which prevents cell cycle entry) offered substantially more therapeutic benefit than concurrent treatment with the drugs. Mechanistically, this is because the CDK4/6 inhibitor prevents cancer cells from repairing the chromosomal damage caused by Taxol. Cancer Cell 10.1016/j.ccell.2020.01.007 (2020).

Abstract A76: Efficacy of immunotherapy agents in patients with metastatic breast cancer treated in phase I clinical trials

Abstract Background: Immuno-oncology (IO) agents have demonstrated exceptional clinical benefit in patients with many tumor types, including melanoma and lung cancer. The PD-L1 inhibitor, atezolizumab, was recently FDA approved in combination with nab-paclitaxel for patients with PD-L1 positive triple-negative breast cancer (TNBC); however, single-agent PD-1/PD-L1 inhibitors demonstrate modest efficacy in breast cancer. The purpose of this study was to investigate the efficacy of IO agents in patients with metastatic breast cancer treated in phase I clinical trials. Methods: We performed a retrospective analysis using a database of patients with metastatic breast cancer who received treatment with IO agents in phase I/Ib clinical trials at the University of Colorado Anschutz Medical Campus from January 1, 2012 to July 1, 2018. Abstracted data included patient demographics, baseline characteristics, and clinical outcomes. Results: 208 patients with metastatic breast cancer were treated in phase I/Ib clinical trials; 43 were treated with an IO agent. The average age was 53 years old and 55.8% had hormone receptor-positive/HER2-negative breast cancer, 39.5% TNBC, and 4.6% HER2-positive disease. On average, patients received two prior lines of chemotherapy (range 0-7) in the metastatic setting. 31/43 patients (72.1%) received single agent or combination IO, and 12/43 (27.9%) received IO + chemotherapy. Median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 12.1 months in all patients. 9/43 (21%) of patients remained on study &amp;gt; 6 months and had a median PFS of 8.6 months. Patients remaining on study &amp;gt; 6 months were more likely to be treated with IO + chemotherapy compared to patients with a PFS &amp;lt; 6 months (77.8% v. 14.7%, p=0.0007). There was no difference in sites of metastasis, prior lines of chemotherapy, breast cancer subtype, absolute lymphocyte count, or LDH between patients with a PFS &amp;gt; 6 months compared to &amp;lt; 6 months. Conclusions: A subset of patients with metastatic breast cancer treated in phase I clinical trials at our center with an IO agent had derived prolonged clinical benefit. The benefit was not limited to patients with TNBC and was associated with receipt of chemotherapy in combination with IO. Predictors of response to immunotherapy in breast cancer beyond PD-L1 expression remain uncharacterized, and further research is needed to identify these factors. Citation Format: Jodi A. Kagihara, Jennifer A. Weiss, Andrew Nicklawsky, Dexiang Gao, Virginia F. Borges, Peter Kabos, Antonio Jimeno, Jennifer R. Diamond. Efficacy of immunotherapy agents in patients with metastatic breast cancer treated in phase I clinical trials [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A76.

Abstract P5-11-20: Efficacy observation of 306 patients with fulvestrant 500mg treatment in hormone-receptor positive HER2 negative metastasis breast cancer, a real world study

Abstract Background: Fulvestrant 500mg has been proved better efficacy in breast cancer with hormone receptor positive (HR+),and then become an optional strategy for primary or second line treatment of HR+ positive metastasis breast cancer (MBC). Methods: In this real world study, we retrospectively analyzed the patients with HR+ HER 2 negative MBC who received fulvestrant 500mg treatment at Beijing cancer hospital during January 2015 to December 2018. Clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS) and adverse events were investigated. Results: There were 306 patients enrolled, median age was 48.7(range 20-75) years, median line of fulvestrant was 2.11(range 1-6), 68.3%(209/306) patients were involved with visceral metastasis. The CBR was 68.6%, median PFS was 8.41m (95%CI: 7.079m-9.743m, range 0.89m-80.16m). Among the patients received fulvestrant at the first line, the PFS was 10.55m(95%CI:6.46m-14.64m, range 0.92m-34.3m). The median OS hasn’t been obtained. In subgroup analysis, the patients without liver metastasis(12.49m vs. 4.60m, p&amp;lt;0.001), small tumor burden(metastasis number 1-2 vs. 3-4 vs. &amp;gt;4, 12.65m vs. 7.72m vs. 3.98m respectively, p&amp;lt;0.001) and experience no or less line of chemotherapy(none vs. 1-2 lines vs. &amp;gt;2 lines, 14.06m vs. 7.79m vs. 3.52m respectively, p&amp;lt;0.001) for metastatic disease were obtained more benefit from fulvestrant treatment. For patients with visceral metastasis, the patients absence of liver metastasis was corelated with longer PFS 9.27m than 4.60m(p&amp;lt;0.001). There were 20(6.54%) adverse events occurred in 306 patients, 95%(19/20) were grade 1-2. The most common adverse event was oral ulcer, and serious adverse events were observed in 1 patients (0.33%) with pulmonary embolism. Conclusions: Fulvestrant was an effective and safe regimen in endocrine therapy for hormone receptor positive HER2 negative MBC. The patients who were in first line treatment, absence of liver metastasis and small tumor burden might be more benefit from fulvestrant. Corresponding authors: Huiping Li, huipingli2012@hotmail.com; Guohong Song, songguohong918@hotmail.com, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital &amp; Institute, 52 Fucheng Rd, Beijing 100142, China Citation Format: Wen Lei, Huiping Li, Guohong Song, Ruyan Zhang, Ran Ran, Ying Yan. Efficacy observation of 306 patients with fulvestrant 500mg treatment in hormone-receptor positive HER2 negative metastasis breast cancer, a real world study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-20.

Abstract P3-10-02: Neutrophil elastase as a therapeutic target to inhibit metastasis in breast cancer

Abstract Background: Chronic inflammation, a hallmark of cancer, is associated with poor prognosis in human various malignancies. Predominantly, tumor associated neutrophils (TANs) and myeloid-derived suppressor cells (MDSCs) are immune cells well characterized to promote inflammation, support tumor growth and metastasis, by secreting chemokines, serine proteases and reactive oxygen species. Increased TANs and MDSCs are predictive markers of both tumor progression and metastasis, suggesting that their inhibition may provide viable anti-tumor strategies. Neutrophil elastase (NE), a serine protease exclusively secreted by TANs and MDSCs, is a crucial mediator of inflammation and tumor progression. Recent preliminary studies from our group suggests that genetic deletion of Elane (encoding NE) inhibits lung metastasis in in vivo models of breast cancer. Yet the precise mechanism(s) by which NE promotes tumorigenesis and metastasis of breast cancer remains to be elucidated. To address this gap in knowledge, the current focus of our work is to identify the tumor-intrinsic and -extrinsic mechanisms by which NE promotes metastasis. Methods: To determine the prognostic significance of NE, we analyzed 192 breast cancer patients (58% ER/PR+ve, 20%-HER-2 +ve and 22% TNBC) for infiltration of TANs. To examine the role of NE in breast cancer metastasis, we have generated Elane+/+ and Elane-/- mice in BALB/c and FVB/N genetic backgrounds, bearing 4T1 and PyMT tumors (orthotopic and spontaneous) respectively. Each of these mouse models develop lung metastasis in 80-90% in tumor-bearing mice within 1-3 months of primary tumor initiation. Results: Immunohistochemical staining of NE, a marker of TANs shows that higher infiltration of NE-positive TANs is associated with recurrence free survival with a hazard ratio of 3.4 (95% CI, 1.1-5.5). Genetic ablation of NE (Elane −/−) in the PyMT and 4T1 models strongly inhibits lung metastasis. Specifically, the number of lung foci was reduced by ~90% in PyMT Elane−/− mice compared to controls (21.8 vs. 2.7, respectively; p=0.0044). Similarly, ~50% decrease in the number of lung foci was observed in the 4T1 Elane−/− mice compared to control (7.8 vs. 3.4, respectively; p=0.0281). Comparison of inflammatory factors in the tumor microenvironment revealed that Csf3 (G-CSF), Cxcr2 (CXCR2) and Cxcl1 (CXCL1/KC) were significantly elevated in tumors from PyMT/4T1 Elane+/+ mice vs. PyMT/4T1 Elane-/- animals. Mechanistically, our result implies NE-dependent recruitment of immunosuppressive subsets (CXCL1 and related chemokines), thus sustaining inflammation at the primary tumor site. NE- dependent secretion of CXCL1 can further enrich for cancer stem-like cells (CSCs) via CXCR2 signaling, thus aiding metastasis. Lastly, we interrogated the efficacy reversible NE inhibitor AZD9668 in Elane+/+ mouse models. 100mg/kg daily treatment of AZD9668 reduced lung metastasis in PyMT mice by 94% compared to vehicle-treated mice (0.49+/- 0.21% vs. 0.03+/-0.01%; p=0.05). Conclusions: Collectively, our studies suggest that genetic and pharmacological ablation of NE reduces metastasis in in vivo models of breast cancer. NE inhibitors thus far have only been clinically tested in COPD patients and their efficacy in breast cancer remains to be evaluated. Our preclinical studies presented here are likely to provide the much needed rationale for the use of this class of NE inhibitors as a viable treatment strategy for the metastatic breast cancer. Citation Format: Amriti Rajender Lulla, Said Akli, Taylor T Chrisikos, Marc A. Pina, Yifan Zhou, Haiyan Li, Stephanie S Watowich, Khandan Keyomarsi. Neutrophil elastase as a therapeutic target to inhibit metastasis in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-02.

Abstract P5-14-23: Preventing alopecia caused by chemotherapy among patients with breast cancer efficacy of applying the cooling hood

Abstract Background: Alopecia is one of the most frequent adverse event of chemotherapy (CHT) in patients with breast cancer (BC). Alopecia causes many unpleasant feelings, as well as emotional disorders, including depression, especially in women Aim: to improve the quality of life among BC patients undergoing CHT. Materials and methods: alopecia prevention procedures were performed by the Cold Caps and Scalp Cooling Systems during various regimens of CHT for 180 BC patients. The mean age of the BC patients was 43 y.o. (from 21 to 73). The alopecia prevention procedure was performed during CHT and included 3 steps: 1. The preventive cooling cycle took 20-30 minutes to achieve required temperature before proceeding medications. 2. The cooling cycle last during whole CHT. 3. The cooling cycle were continued after CHT and took from 60 to 120 minutes. The duration of post-CHT cycle was dependent on the type of drug and the period of excretion. Patients received various regimens of CHT, including: antracyclins (47%), taxanes (32%), Cisplatin (5%), Gemcitabine (3,5%), AT (3,5%), CP (9%). Local hypothermia during various regimens of CHT (n= 988). Regimens of CHTPatients, n=180Cycles, n= 988n cycles per patientАT (doxorubicin + paclitaxel)6355 (2-6)АС (doxorubicin + cyclophosphamide)864474 (2-6)СР (Carboplatin+ Paclitaxel)15201 (1-4)Paclitaxel584407 (4-12)Cisplatin9302 (2-4)Gemcitabine6162 (2-4) Alopecia degree evaluated based on СТСАЕ 4.0: I degree - hair loss of &amp;lt;50% of normal for that individual that is not obvious from a distance but only on close inspection; a different hair style may be required to cover the hair loss but it does not require a wig or hair piece to camouflage. II degree - hair loss of &amp;gt;=50% normal for that individual that is readily apparent to others; a wig or hair piece is necessary if the patient desires to completely camouflage the hair loss; associated with psychosocial impact. Results: Among BC patients who were given antracyclins (n=86), 62 (72%) had I degree alopecia, 24 (28%) - II degree alopecia. Among patients who were given taxanes (n=58), 56 (96%) suffered from I degree alopecia, in 2 (4%) of them developed II degree alopecia. Patients who received treatment with Cisplatin (n=9), 7 (78%) of them had I degree alopecia and 2 - II degree alopecia (22%); patients with gemcitabine-based CHT (n=6), suffered from I degree alopecia in 100%. Patients with AT (n=6), had I degree alopecia in 3 (50%) patients, 3 (50%) suffered from II degree alopecia. In regimens like CP (n=15), 8 (53%) had I degree alopecia, 7 (47%) - II degree alopecia. Side effects after procedure: 5 (2,8%) patients had headaches, procedure was discontinued for 3 (1,7%) patients because of intolerance to low temperatures. Conclusions: hypothermia of the hairy part of the head is an effective method of preventing alopecia among BC patients during chemotherapy with antracyclins (72% of cases), taxanes (96%), Cisplatin (78%) and with gemcitabine (100%). Citation Format: Veronika Klimenko, Tatiana Semiglazova, Boris Kasparov, Anton Krutov, Margarita Zernova, Kristina Kondrateva, Valeria Kluge, Evgenia Kharchenko, Artem Poltoratsky, Karina Khidishyan, Vladislav Semiglazov, Roman Donskih, Petr Krivorotko, Vladimir Semiglazov, Aleksey Belyaev. Preventing alopecia caused by chemotherapy among patients with breast cancer efficacy of applying the cooling hood [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-23.

HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration.

NAD+-dependent SIRT7 deacylase plays essential roles in ribosome biogenesis, stress response, genome integrity, metabolism and aging, while how it is transcriptionally regulated is still largely unclear. TGF-β signaling is highly conserved in multicellular organisms, regulating cell growth, cancer stemness, migration and invasion. Here, we demonstrate that histone deacetylase HDAC8 forms complex with SMAD3/4 heterotrimer and occupies SIRT7 promoter, wherein it deacetylates H4 and thus suppresses SIRT7 transcription. Treatment with HDAC8 inhibitor compromises TGF-β signaling via SIRT7-SMAD4 axis and consequently, inhibits lung metastasis and improves chemotherapy efficacy in breast cancer. Our data establish a regulatory feedback loop of TGF-β signaling, wherein HDAC8 as a novel cofactor of SMAD3/4 complex, transcriptionally suppresses SIRT7 via local chromatin remodeling and thus further activates TGF-β signaling. Targeting HDAC8 exhibits therapeutic potential for TGF-β signaling related diseases.

A Recepto-Informatics Study of the Natural Nutraceuticals having Potential Anticancer Efficacy for Breast Cancer

A Recepto-Informatics Study of the Natural Nutraceuticals having Potential Anticancer Efficacy for Breast Cancer

Histone Signatures Predict Therapeutic Efficacy in Breast Cancer.

Objective: Regulatory abnormalities caused by chromatin modifications are being increasingly recognized as contributors to cancer. While many molecularly targeted drugs have the potential to revert these modifications, their precise mechanism of action in cellular reprogramming is not known. Methods: To address this, we introduce an integrated phosphoprotein-histone-drug network (iPhDNet) approach to generate “global chromatin fingerprints of histone signatures.” The method integrates proteomic/phosphoproteomic, transcriptomic and regulatory genomic data to provide a causal mechanistic network and histone signatures of drug response. Results: We demonstrate the utility of iPhDNet in identifying H3K27me3K36me3 histone mark as a key fingerprint of response, mediated by chromatin remodelers BRD4, NSD3, EZH2, and a proto-oncogene MYC when treated with CDK inhibitors. Conclusions: We construct a regulatory network of breast cancer response to treatment and show that histone H3K27me3K36me3 status changes, driven by the BRD4/MYC pathway, upon treatment with drugs are hallmarks of response to treatment.

Pharmacodynamics effects of CDK4/6 inhibitor LEE011 (ribociclib) in high-risk, localised prostate cancer: a study protocol for a randomised controlled phase II trial (LEEP study: LEE011 in high-risk, localised Prostate cancer)

IntroductionDespite the development of new therapies for advanced prostate cancer, it remains the most common cause of cancer and the second leading cause of cancer death in men. It is...

Nanomedicine in treatment of breast cancer - A challenge to conventional therapy.

Amongst the various types of cancer, breast cancer is a highly heterogeneous disease and known as the leading cause of death among women globally. The extensive interdisciplinary investigation in nanotechnology and cancer biomedical research has been evolved over the years for its effective treatment. However, the advent of chemotherapeutic resistance in breast cancer is one of the major confront researchers are facing in achieving successful chemotherapy. Research in the area of cancer nanotechnology over the years have now been revolutionized through the development of smart polymers, lipids, inorganic materials and eventually their surface-engineering with targeting ligands. Moreover, nanotechnology further extended and brings in the notice the new theranostic approach which combining the therapy and imaging simultaneously. Currently, research is being envisaged in the area of novel nano-pharmaceutical design viz. liposome, nanotubes, polymer lipid hybrid system, which focuses to make the chemotherapy curative and long-lasting. In this review, we aimed to discuss the recent advancement of different surface-engineered/targeted nanomedicines that improved the drug efficacy in breast cancer.