Animal Models Of Breast Cancer Research Articles

Intraoperative near-infrared imaging can identify canine mammary tumors, a spontaneously occurring, large animal model of human breast cancer.

IntroductionCurrent methods of intraoperative margin assessment in breast conserving surgery are impractical, unreliable, or time consuming. We hypothesized that intraoperative near-infrared (NIR) imaging with an FDA-approved NIR optical contrast agent could identify canine mammary tumors, a spontaneous large animal model of human breast cancer, during surgery.MethodsDogs with mammary tumors underwent a standard of care lumpectomy or mastectomy with wide surgical margins 20 hours after indocyanine green administration (3 mg/kg IV). During surgery, NIR imaging was performed on tumors and wound margins in situ and tumors and lymph nodes ex vivo. Following resection, the wound bed was examined for residual fluorescence. Fluorescence intensity was determined by signal-to-background ratio (SBR). All tumors, areas of residual fluorescence, and lymph nodes underwent histopathologic analysis.ResultsThere were 41 mammary tumors in 16 female dogs. Twenty tumors were malignant and 21 were benign. Twenty-eight tumors were fluorescent (mean SBR 1.5±0.2). Sensitivity of fluorescence for all malignant tumors was 80% (16/20) and 93.3% (14/15) for malignant tumors > 2 cm. Specificity for malignancy was low (< 2cm = 55%; > 2cm = 30%). Tumors > 2 cm were more likely to be fluorescent (OR 6.05, 95% CI 1.50–24.44, P = 0.011) but not more likely to be malignant (OR 3.09, 95% CI 0.86–11.14, P = 0.085) than tumors ≤ 2 cm. Four out of seven inguinal lymph nodes excised in the mastectomy specimen fluoresced. All four drained malignant tumors; however only 2/4 contained metastatic disease.ConclusionSystemic ICG accumulates reliably in malignant canine mammary tumors > 2 cm. Although no tumor margins fluoresced, a wider margin of normal tissue is removed in canine mastectomy, making direct comparisons with breast conserving surgery difficult. Targeted NIR imaging agents are likely required to improve detection of smaller tumors and improve the specificity of NIR imaging for residual disease and metastatic lymph node detection.

Ibrutinib in Gynecological Malignancies and Breast Cancer: A Systematic Review.

Ibrutinib is an orally available, small-molecule tyrosine kinase inhibitor. Its main purpose is to inhibit Bruton’s tyrosine kinase (BTK), an enzyme that is crucial in B cell development. It is FDA approved for the treatment of certain hematological malignancies. Several promising off-target drug effects have led to multiple, mostly preclinical investigations regarding its use in solid tumors. Unfortunately, data on its effectiveness in gynecological malignancies are limited, and (systematic) reviews are missing. The objective of this review was to summarize the existing literature and to analyze the evidence of ibrutinib as a treatment option in gynecological malignancies, including breast cancer. Studies were identified in MEDLINE and EMBASE using a defined search strategy, and preclinical or clinical research projects investigating ibrutinib in connection with these malignancies were considered eligible for inclusion. Our findings showed that preclinical studies generally confirm ibrutinib’s efficacy in cell lines and animal models of ovarian, breast, and endometrial cancer. Ibrutinib exerts multiple antineoplastic effects, such as on-target BTK inhibition, off-target kinase inhibition, and immunomodulation by interference with myeloid-derived suppressor cells (MDSCs), programmed death-ligand 1 (PD-L1), and T cell response. These mechanisms were elaborated and discussed in the context of the evidence available. Further research is needed in order to transfer the preclinical results to a broader clinical appliance.

Efficacy of co-immunization with the DNA and peptide vaccines containing SYCP1 and ACRBP epitopes in a murine triple-negative breast cancer model

ABSTRACT Multiepitope cancer vaccines have gained lots of attention for prophylactic and therapeutic purposes in cancer patients. In our previous study, multiepitope DNA and peptide cancer vaccines consisted of the most immunodominant epitopes of ACRBP and SYCP1 antigens were designed by bioinformatic tools. In this study, the effect of prophylactic co-immunization with these DNA and peptide cancer vaccines in the 4T1 breast cancer animal model was assessed. Serum levels of the peptide-specific IgG total, IgG2a and IgG1 were measured by enzyme-linked immunosorbent assay (ELISA). Also, the efficacy of the immunized mice splenocytes’ for producing interleukin-4 (IL-4) and interferon-γ (IFN-γ) was evaluated. The co-immunization caused a significant (P < .05) increase in the serum levels of IgG1 and IgG2a. The co-immunized mice splenocytes exhibited significantly enhanced IL-4 (6.6-fold) and IFN-γ (19-fold) production. Also, their lymphocytes exhibited higher proliferation rate (3-fold) and granzyme B production (6.5-fold) in comparison with the control. The prophylactic co-immunization significantly decreased the breast tumors’ volume (78%) and increased the tumor-bearing mice survival time (37.5%) in comparison with the control. Taking together, prophylactic co-immunization with these multiepitope DNA and peptide cancer vaccines can activate the immune system against breast cancer. However, further experiments are needed to evaluate their efficacy from different angles.

[Value of Thermal Tomography in Early Diagnosis of Breast Cancer in Animal Models].

Objective To obtain ultrasound and thermal tomography images of breast cancer during its growth and to assess the value of thermal tomography in detecting breast cancer. Methods Breast cancer models were established with NOD/SCID mice and SD rats. These animal models were examined by thermal tomography,plain ultrasound,and contrast-enhanced ultrasound. Tumor tissues were stained with CD34 to explore the relationship between tumor heat production and vascular pathology. Results Thermal tomography detected breast cancer 2-4 days earlier than ultrasound. The expression of CD34 in tumor tissues was increased,along with thickened,increased,and irregular blood vessels. Conclusion Thermal tomography can detect early breast cancer and is a promising tool for screening breast cancer.

Low Doses of Thymoquinone and Ferulic Acid in Combination Effectively Inhibit Proliferation of Cultured MDA-MB 231 Breast Adenocarcinoma Cells

Thymoquinone (TQ) and Ferulic Acid (FA) are natural ingredients from Nigella sativa and Ferula asafetida, respectively. Individually both TQ and FA have shown anticancer properties in a variety of cancer cell lines. We investigated the combination effect of lower doses of TQ and FA on proliferation, apoptosis, and cell cycle of a breast cancer cell line MDA-MB 231. Cells were treated with various concentrations of TQ, FA and various combinations of TQ + FA for 48 hrs. Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyltetrazolium bromide (MTT) assay, whereas cell cycle and apoptosis were measured with flow-cytometry after propidium iodide staining and Annexin-V/FITC staining, respectively. TQ (50 and 100 µM) and FA (450 µM), and all the doses of TQ and FA in combination significantly decreased cell proliferation. 25 µM TQ and 250 µM FA individually did not affect cell proliferation but in combination significantly reduced cell proliferation. TQ at 50 µM caused significant apoptosis, whereas, FA did not affect apoptosis. These in vitro data suggest that in combination, relatively lower doses of TQ and FA are effective in decreasing cancer cell proliferation, and thus have anticancer therapeutic potential. Further research is needed to corroborate these findings in an animal model of breast cancer.

Activation of Canonical BMP4-SMAD7 Signaling Suppresses Breast Cancer Metastasis.

Metastasis is the major cause of death in patients with cancer; with no therapeutic cure, treatments remain largely palliative. As such, new targets and therapeutic strategies are urgently required. Here, we show that bone morphogenetic protein-4 (BMP4) blocks metastasis in animal models of breast cancer and predicts improved survival in patients. In preclinical models of spontaneous metastasis, BMP4 acted as an autocrine mediator to modulate a range of known metastasis-regulating genes, including Smad7, via activation of canonical BMP-SMAD signaling. Restored BMP4 expression or therapeutically administered BMP4 protein, blocked metastasis and increased survival by sensitizing cancer cells to anoikis, thereby reducing the number of circulating tumor cells. Gene silencing of Bmp4 or its downstream mediator Smad7, reversed this phenotype. Administration of recombinant BMP4 markedly reduced spontaneous metastasis to lung and bone. Elevated levels of BMP4 and SMAD7 were prognostic for improved recurrence-free survival and overall survival in patients with breast cancer, indicating the importance of canonical BMP4 signaling in the suppression of metastasis and highlighting new avenues for therapy against metastatic disease. SIGNIFICANCE: Targeting the BMP4-SMAD7 signaling axis presents a novel therapeutic strategy to combat metastatic breast cancer, a disease that has had no reduction in patient mortality over 20 years. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/6/1304/F1.large.jpg.

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer

PurposeThe combination of targeting the CDK4/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER-positive breast cancer. However, the poor physicochemical properties of fulvestrant require monthly intramuscular injections to patients, which limit the pharmacokinetic and pharmacodynamic activity of the compound. Therefore, an orally available compound that more rapidly reaches steady state may lead to a better clinical response in patients. Here, we report the identification of G1T48, a novel orally bioavailable, non-steroidal small molecule antagonist of ER.MethodsThe pharmacological effects and the antineoplastic mechanism of action of G1T48 on tumors was evaluated using human breast cancer cells (in vitro) and xenograft efficacy models (in vivo).ResultsG1T48 is a potent and efficacious inhibitor of estrogen-mediated transcription and proliferation in ER-positive breast cancer cells, similar to the pure antiestrogen fulvestrant. In addition, G1T48 can effectively suppress ER activity in multiple models of endocrine therapy resistance including those harboring ER mutations and growth factor activation. In vivo, G1T48 has robust antitumor activity in a model of estrogen-dependent breast cancer (MCF7) and significantly inhibited the growth of tamoxifen-resistant (TamR), long-term estrogen-deprived (LTED) and patient-derived xenograft tumors with an increased response being observed with the combination of G1T48 and the CDK4/6 inhibitor lerociclib.ConclusionsThese data show that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER-positive breast cancer.

Reduction of Breast Cancer Lymph Node Metastasis by Nano-Carbon Absorption of 5-Fluorouracil

To observe the clinical effect of nano-carbon adsorption of 5-fluorouracil (5-FU) on Breast cancer lymph node metastasis in New Zealand rabbits. A breast cancer animal model was established by local injection of a VX2 tumor tissue suspension in thirty New Zealand rabbits. An observation group, control group A, and control group B were established using a random number table, with ten rabbits in each group. Once tumors with a diameter ≥5 mm were identified in the lymph nodes, the animals received the intervention. The observation group had nano-carbon-5-FU suspension subcutaneously injected, control group A had 5-FU subcutaneously injected through the ear margin, and control group B had 5-FU subcutaneously injected; all received a drug dose of 30 mg · kg–1. Half of the animals in the three groups were killed following treatment for thirty minutes, while the rest of the animals were killed following treatment for seven days. Tumors and lymphatic metastases were removed. Tumor and lymphatic metastasis volume were compared. H&amp;E stained sections were used to determine the ND of tumor cells. A dTUP TUNEL assay using Terminal Deoxynucleotidyl Transferase (TdT) was used to assess tumor cell apoptosis. The expression level of casapase-3 mRNA in tumors and lymphoid tissues was determined using RT-PCR. After treatment for 30 mins, the observation group exhibited a significantly higher 5-FU concentration in lymph node metastases, and significantly lower 5-FU concentrations in plasma and tumors. Nano-carbon can increase the 5-FU concentration in tumor tissue, as well as enhance the clinical effect of drugs on lymph node metastases.

Cancer Cell-derived Secretory Factors in Breast Cancer-associated Lung Metastasis: Their Mechanism and Future Prospects.

In Breast cancer, Lung is the second most common site of metastasis after the bone. Various factors are responsible for Lung metastasis occurring secondary to Breast cancer. Cancer cell-derived secretory factors are commonly known as ‘Cancer Secretomes’. They exhibit a prompt role in the mechanism of Breast cancer lung metastasis. They are also major constituents of host-associated tumor microenvironment. Through cross-talk between cancer cells and the extracellular matrix components, cancer cell-derived extracellular matrix components (CCECs) such as hyaluronan, collagens, laminin and fibronectin cause ECM remodeling at the primary site (breast) of cancer. However, at the secondary site (lung), tenascin C, periostin and lysyl oxidase, along with pro-metastatic molecules Coco and GALNT14, contribute to the formation of pre-metastatic niche (PMN) by promoting ECM remodeling and lung metastatic cells colonization. Cancer cell-derived secretory factors by inducing cancer cell proliferation at the primary site, their invasion through the tissues and vessels and early colonization of metastatic cells in the PMN, potentiate the mechanism of Lung metastasis in Breast cancer.On the basis of biochemical structure, these secretory factors are broadly classified into proteins and non-proteins. This is the first review that has highlighted the role of cancer cell-derived secretory factors in Breast cancer Lung metastasis (BCLM). It also enumerates various researches that have been conducted to date in breast cancer cell lines and animal models that depict the prompt role of various types of cancer cell-derived secretory factors involved in the process of Breast cancer lung metastasis. In the future, by therapeutically targeting these cancer driven molecules, this specific type of organ-tropic metastasis in breast cancer can be successfully treated.

Cannabinoids and Hormone Receptor-Positive Breast Cancer Treatment.

Breast cancer (BC) is the most common cancer in women worldwide. Approximately 70–80% of BCs express estrogen receptors (ER), which predict the response to endocrine therapy (ET), and are therefore hormone receptor-positive (HR+). Endogenous cannabinoids together with cannabinoid receptor 1 and 2 (CB1, CB2) constitute the basis of the endocannabinoid system. Interactions of cannabinoids with hypothalamic–pituitary–gonadal axis hormones are well documented, and two studies found a positive correlation between peak plasma endogenous cannabinoid anandamide with peak plasma 17β-estradiol, luteinizing hormone and follicle-stimulating hormone levels at ovulation in healthy premenopausal women. Do cannabinoids have an effect on HR+ BC? In this paper we review known and possible interactions between cannabinoids and specific HR+ BC treatments. In preclinical studies, CB1 and CB2 agonists (i.e., anandamide, THC) have been shown to inhibit the proliferation of ER positive BC cell lines. There is less evidence for antitumor cannabinoid action in HR+ BC in animal models and there are no clinical trials exploring the effects of cannabinoids on HR+ BC treatment outcomes. Two studies have shown that tamoxifen and several other selective estrogen receptor modulators (SERM) can act as inverse agonists on CB1 and CB2, an interaction with possible clinical consequences. In addition, cannabinoid action could interact with other commonly used endocrine and targeted therapies used in the treatment of HR+ BC.

Pracinostat (SB939), a histone deacetylase inhibitor, suppresses breast cancer metastasis and growth by inactivating the IL-6/STAT3 signalling pathways

AimsHistone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying molecular mechanisms. Main methodsMTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the molecular mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 subcutaneous tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects. Key findingsOur results demonstrated that SB939 at 0.5–1 μmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models. SignificanceOur findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.

PERITUMOURAL MUM1+ Plasma Cells are Associated With Poor Outcomes in Cats With Invasive Mammary Carcinoma, Spontaneous Immunocompetent Animal Models of Breast Cancer

PERITUMOURAL MUM1+ Plasma Cells are Associated With Poor Outcomes in Cats With Invasive Mammary Carcinoma, Spontaneous Immunocompetent Animal Models of Breast Cancer

Breast cancer animal models and applications.

Breast cancer is the most common malignancy in women. Basic and translational breast cancer research relies heavily on experimental animal models. Ideally, such models for breast cancer should have commonality with human breast cancer in terms of tumor etiology, biological behavior, pathology, and response to therapeutics. This review introduces current progress in different breast cancer experimental animal models and analyzes their characteristics, advantages, disadvantages, and potential applications. Finally, we propose future research directions for breast cancer animal models.

The effect of opine on matrix metalloproteinase expression in mice with breast cancer

Regarding the anti-inflammatory and anti-tumour effects of arginine and its derivatives, this study evaluates matrix metalloproteinase (MMPs) expression in an animal model of breast cancer following administration of octopine. In this study, 40 animals of Balb/C mice were divided into 5 groups: the healthy control, the cancer control, the cancer group receiving 50 mg of octopine, the cancer group receiving 100 mg of octopine and the cancer group receiving 150 mg of octopine for 3 weeks. 4T1 cell line was used to induce cancer. Biopsy specimens were enrolled from mice and MMP-1, MMP-3 and MMP-9 gene expression evaluated using real-time PCR, while these protein amounts were measured using immunohistochemistry and ELISA methods. Data were analysed using one-way ANOVA, Kruskal-Wallis and Mann–Whitney U tests (p < .05). The results showed that 100 mg octopine consumption had significant decreasing effect on MMP-9 expression (p = .02) in the treatment group compared with cancerous non-treated mice. Furthermore, results from immunohistochemistry and ELISA confirmed this effect, the protein amount of MMP-9 was significantly decreased in group treating with 100 mg octopine (.005). The use of octopine has a beneficial effect on reducing MMP-9 in mice breast cancer.

Carcinogenic potential of fluorinated estrogens in mammary tumorigenesis

Fluorination preventing metabolic hydroxylation of 17β-estradiol (E2) was applied to investigate the mechanisms underlying estrogen-induced carcinogenesis. Either 2-fluoro-17β-estradiol (2-FE2) or 4-fluoro-17β-estradiol (4-FE2) was administered subcutaneously for 52 weeks to August Copenhagen Irish (ACI) rats, the preferred animal model for human breast cancer. 4-FE2 induced frequent mammary tumors whereas 2-FE2 did not. The cumulative incidence of mammary tumors in rats treated with 4-FE2 was comparable to that observed with E2. The carcinogenic results were supported by histological examination of mammary glands of fluorinated estrogen-treated ACI rats. To evaluate the estrogenic potential of the fluorinated estrogens, 2-FE2 or 4-FE2 was administrated subcutaneously to ovariectomized rats. Both 4-FE2 and 2-FE2 showed high uterotrophic potency. Our results indicate that estrogenic potential may not be the sole factor driving mammary tumorigenesis. Since fluorination inhibits metabolic hydroxylation of E2 at the substituted position, the carcinogenic effect may occur through the metabolic activation of 2-hydroxylated E2, in combination with the compound’s estrogenic potency.

465P - A phase I open label dose escalation trial evaluating VT1021 in patients with advanced solid tumours

BackgroundVT1021 is a cyclic pentapeptide that functions as a potent inducer of thrombospondin-1 (Tsp-1) expression in the tumor microenvironment (TME). By triggering the production of Tsp-1, VT1021 reprograms the TME from one that is immune-suppressive and tumor-promoting, to one that activates the adaptive immune system and is tumor-inhibiting. Tsp-1 reprograms the TME to: (i) induce apoptosis in tumor cells that express CD36 on their cell surface, (ii) convert macrophages from M2 to M1 polarization, which promotes phagocytosis and blunts immunosuppression, and (iii) inhibit angiogenesis. Preclinical studies have shown robust anti-tumor activities of VT1021 in animal models of ovarian, pancreatic and breast cancer, including complete tumor regression and reprogramming of the immune TME. MethodsThis study is a first-in-human, phase 1, open-label, multicenter dose escalation (Part 1) study with dose expansion (Part 2) in advanced solid tumors. The primary objectives are to assess the safety and tolerability of VT1021, assess dose-limiting toxicities (DLT), and determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). Secondary objectives include the evaluation of pharmacokinetics (PK) and the pharmacodynamic (PD) effects of VT1021 in tumor biopsies, and assessment of preliminary efficacy. ResultsIn Part 1 of the study, 27 patients received 0.5-6.6mg/kg of VT1021 twice weekly to determine the MTD and RP2D for expansion. One patient developed a grade 3 infusion reaction and 2 patients developed a grade 2 infusion reaction. Premedication with steroids and antihistamines has prevented subsequent significant infusion reactions. Other drug-related AEs included grade 1-2 fatigue, myalgia and dizziness. Dose proportionality was observed in PK analysis. Evidence of Tsp-1 expression, as measured by IHC on tumor biopsies, was observed. Prolonged stable disease was observed in 2 patients including ovarian and colorectal cancer. In Part 2 of the study, 75 patients will be enrolled based on tumor type and CD36 expression. ConclusionsThrough all doses tested thus far, VT1021 has been shown to be safe for patients and induces expression of Tsp-1. Clinical trial identificationNCT03364400 December 6, 2017. Legal entity responsible for the studyVigeo Therapeutics, Inc. FundingVigeo Therapeutics, Inc. DisclosureS. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Vigeo Therapeutics, Inc. K. Kerstein: Full / Part-time employment: Vigeo Therapeutics, Inc. G. Berk: Advisory / Consultancy: Vigeo Therapeutics, Inc. M.J. Cieslewicz: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Vigeo Therapeutics. J. Watnick: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Vigeo Therapeutics, Inc. All other authors have declared no conflicts of interest.

349P - Polo-like kinase 1 inhibitor onvansertib synergizes with paclitaxel in breast cancer carrying p53 mutation

BackgroundSomatic mutation in TP53 gene (mutp53) is a strong prognostic marker in breast cancer. Triple negative breast cancer (TNBC) is characterized by up to 80% mutp53 and the greatest overall genomic instability among subtypes. Polo-like kinase 1 (PLK1) regulates progression of cells through the G2 phase of the cell cycle. We hypothesize that mutp53 in the context of breast cancer can predict synergy to paclitaxel [p] plus onvansertib [o], an orally available highly selective Plk1 inhibitor. MethodsDrugs were tested in a set of mutp53 breast cancer cells including TNBC SUM149 and SUM159, luminal SUM52 and T47D, and wtp53 TNBC SUM1315, luminal MCF7, and normal breast MCF10A. We performed cell proliferation assays in order to determine the IC50 (Inhibition Concentration of 50%) for each drug. Synergism was determined using the Chou-Talalay method, by determining the combination index (CI). Apoptosis was determined by PARP cleavage proteins detection in cells synchronized with double thymidine block. For the in vivo experiments, mice were injected with 5x106 SUM159 cells and randomly assigned to experimental condition (control, o, p, o+p). The primary endpoint was tumor volume (TV) measured longitudinally. We performed one-sided two-samples Wilcoxon test comparing the means of the adjusted TV measured at 10 days for p and o+p. ResultsTNBC cells were more sensitive to single agent o compared to luminal cells. Breast cell lines with mutp53 (SUM149, SUM159, SUM52 and T47D) were found to have Combination Index (CI) < 1 when treated with o+p. Conversely, in cell line with wtp53 (SUM1315, MCF7, and MCF10A), o+p did not show synergy, CI≥1. Western blot showed prolonged apoptosis for PLK1 inhibition plus taxane compared to PLK1 inhibitor alone, in SUM149 and SUM159. In the xenograft model SUM159, the adjusted 10-day TV for o+p was significantly less than TV for p, p-value = 0.0303. ConclusionsOnvansertib in combination with paclitaxel showed promising results in a subset of breast cancer cells and animal model characterized by the presence of mutp53. Our preclinical results confirm mutp53 as predictive biomarker of synergy and set the feasibility of performing a clinical trial with the combination o+p for mutp53 breast cancer patients. Legal entity responsible for the studyThe authors. FundingK12 Paul Calabresi funding, K12 CA157688. DisclosureM. Erlander: Leadership role, Chief Scientific Officer (CSO): Trovagene Oncology. All other authors have declared no conflicts of interest.

Remodeling the Tumor Microenvironment Sensitizes Breast Tumors to Anti-Programmed Death-Ligand 1 Immunotherapy.

Immunotherapies targeting immune checkpoint inhibitors have changed the landscape of cancer treatment, however, many patients are resistant or refractory to immunotherapy. The sensitivity of tumor cells to immunotherapy may be influenced by hyaluronan (HA) accumulation in the tumor microenvironment (TME). Enzymatic degradation of HA by pegvorhyaluronidase alfa (PEGPH20; PVHA) remodels the TME. This leads to reduced tumor interstitial pressure and decompressed tumor blood vessels, which are both associated with increased exposure of tumor cells to chemotherapy drugs. Here, we demonstrate PVHA increased the uptake of anti-programmed death-ligand 1 (PD-L1) antibody in HA-accumulating animal models of breast cancer. The increased levels of anti-PD-L1 antibody were associated with increased accumulation of T cells and natural killer cells and decreased myeloid-derived suppressor cells. PD-L1 blockade significantly inhibited tumor growth when combined with PVHA, but not alone. Our results suggest that PVHA can sensitize HA-accumulating tumors to anti-PD-L1 immunotherapy. SIGNIFICANCE: These findings show removal of hyaluronan in the tumor microenvironment improves immune cells and checkpoint inhibitors access to tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4149/F1.large.jpg.

Abstract 1492: Evaluation of combinatorial chemotherapeutics nano-carriers at different dosage regimens in breast cancer model: Tumor immune signaling, inhibit angiogenesis and tumor growth

Abstract The objective of this work is to evaluate the effect of individual &amp; combinatorial delivery of Docetaxel (DTX) and Everolimus (EVR) in polymeric micelles at frequent dosing regimen below their maximum tolerated dose on angiogenesis, efficacy &amp; immune signaling in breast cancer animal model. Based on previous in-vivowork in our lab, the maximum tolerated dose (MTDs) for EVR, DTX &amp; combinatorial micelles is 50, 25 and 20 mg/kg respectively. To achieve our goal, two studies have been conducted. First, in-vivo assessment of anti-angiogenic effects of individual &amp; dual DTX-EVR micelles in murine model at 10%, 30%, and 50% MTD, &amp; MTD dose. Second, in-vivo efficacy evaluation of individual &amp; dual DTX EVR micelles at 10%, 30%, 50% MTD, and MTD dose in orthotropic breast cancer murine model. Relative blood vessel invasion &amp; increase in tumor growth will be evaluated for each dosing treatment. We observed that dual DTX EVR polymeric micelles showed significant inhibition of angiogenesis &amp; tumor growth compared to individual agent. The effect of frequent lower dosing schedule is also currently being investigated for its effect immune signaling. Citation Format: Adel Al Fatease, Vidhi Shah, Kalei Lopez, Brianna Cote, Deepa Rao, Adam Alani. Evaluation of combinatorial chemotherapeutics nano-carriers at different dosage regimens in breast cancer model: Tumor immune signaling, inhibit angiogenesis and tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1492.

Inhibition of ERRα Prevents Mitochondrial Pyruvate Uptake Exposing NADPH-Generating Pathways as Targetable Vulnerabilities in Breast Cancer

Most cancer cells exhibit metabolic flexibility, enabling them to withstand fluctuations in intratumoral concentrations of glucose (and other nutrients) and changes in oxygen availability. While these adaptive responses make it difficult to achieve clinically useful anti-tumor responses when targeting a single metabolic pathway, they can also serve as targetable metabolic vulnerabilities that can be therapeutically exploited. Previously, we demonstrated that inhibition of estrogen-related receptor alpha (ERRα) significantly disrupts mitochondrial metabolism and that this results in substantial antitumor activity in animal models of breast cancer. Here we show that ERRα inhibition interferes with pyruvate entry into mitochondria by inhibiting the expression of mitochondrial pyruvate carrier 1 (MPC1). This results in a dramatic increase in the reliance of cells on glutamine oxidation and the pentose phosphate pathway to maintain nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis. In this manner, ERRα inhibition increases the efficacy of glutaminase and glucose-6-phosphate dehydrogenase inhibitors, a finding that has clinical significance.