Background: Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with a high metastatic rate. Despite significant advances in breast cancer therapeutics, due to the lack of specific therapeutic targets in TNBC, cytotoxic chemotherapy is still the mainstay of treatment for this BC subtype. Preclinical studies have shown that the Receptor for Advanced Glycation End-products (RAGE) drives the progression and metastasis of aggressive cancer subtypes, including TNBC. RAGE plays a multifaceted role in driving tumorigenesis and metastasis through tumor cell-intrinsic mechanisms, such as cancer cell invasion, migration and epithelial-mesenchymal transition, and tumor cell-extrinsic mechanisms. This multifaceted role in cancer progression and metastasis makes RAGE a promising therapeutic target in the prevention and treatment of breast cancer. Here we tested the preclinical anti-metastasic efficacy of two small molecule RAGE inhibitors; TTP48 (Azeliragon) and FPS-ZM1. Importantly, TTP488 displays a high safety profile in human trials and has previously undergone Phase 3 clinical trials for Alzheimer’s disease. While FPS-ZM1 is a well-known RAGE inhibitor in preclinical cancer models, TTP488 has not been tested for its anti-cancer activity in breast cancer. Methods: We tested the in vitro anti-metastatic effect of TTP488 and FPS-ZM1 on cancer cell migration and invasion in Boyden chamber assays with TNBC cell lines (MDA-MB-231 and 4T-1). We used the 4175 highly metastatic MDA-MB-231 variant in xenograft studies in NSG mice to test the efficacy of the RAGE inhibitors in vivo on tumor progression and metastasis. Experimental metastasis assays were performed with tail-vein injection of 4T-1 cells into BALBc mice. We performed bulk RNA sequencing on the MDA-MB-231/4175/NSG tumors to unveil and compare the mechanism of action of the two small molecule RAGE inhibitors. Results: Our results showed that TTP488 and FPS-ZM1 impaired mechanisms of metastasis in vitro with both MDA-MB231/4175 and 4T-1 cells. TTP488 and FPS-ZM1 significantly inhibited MDA-MB231/4175 cell metastasis from the orthotopic site in NSG mice without displaying any deleterious effects on mouse health. In the syngeneic 4T-1/BALBc model, both TTP488 and FPS-ZM1 impaired metastasis in tail-vein injected experimental metastasis assays. Transcriptomic analysis of primary xenograft tumors from NSG mice revealed that TTP488 and FPS-ZM1 displayed high concordance in gene expression changes. Pathway enrichment analysis showed that both RAGE inhibitors affected metastatic pathways, including focal adhesion, ECM-receptor interaction, cell cycle, and DNA replication. Conclusions: These results show that TTP488 impairs metastasis of multiple highly aggressive TNBC models for the first time. Importantly, as TTP488 displays a high safety profile in human trials, this study provides the rationale for evaluating TTP488 in clinical trials to treat or prevent metastatic breast cancer. Citation Format: Melinda Magna, Gyong Ha Hwang, Alec McIntosh, Katherine Drews-Elger, Masaru Takabatake, Barbara Mera, Taekyoung Kwak, Philip Miller, Marc Lippman, Barry I. Hudson. Azeliragon (TTP488), an orally- available small molecule RAGE inhibitor, reduces metastasis in preclinical mouse models of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-10.

The present study aimed to evaluate the yearly number of Colles’ fractures in Italy from 2001 to 2016, based on official information found in hospitalization records. A secondary aim was to estimate the average length of hospitalization for patients with a Colles’ fracture. A tertiary aim was to investigate the distribution of the procedures generally performed for Colles’ fractures’ treatment in Italy. An analysis of the National Hospital Discharge records (SDO) maintained at the Italian Ministry of Health, concerning the 15 years of our study (from 2001 to 2016) was performed. Data are anonymous and include the patient’s age, sex, domicile, length of hospital stays (days), primary diagnoses and primary procedures. From 2001 to 2016, 120,932 procedures for Colles’ fracture were performed in Italy, which represented an incidence of 14.8 procedures for every 100,000 adult Italian inhabitants. The main number of surgeries was found in the 65–69- and 70–74-year age groups. In the present study, we review the epidemiology of Colles’ fractures in the Italian population, the burden of the disease on the national health care system (in terms of length of hospitalization) and the distribution of the main surgical procedures performed for the treatment of the disease.

Background: Breast cancer (BC) is treatable with early detection, but once metastasis occurs, there is no cure. Therefore, it is of upmost importance to find targetable biomarkers that are involved in modulating the multi-step metastatic process. The Receptor for Advanced Glycation Endproducts (RAGE) and its ligands are an inflammatory pathway that are involved in modulating breast cancer progression and metastasis. We recently demonstrated that genetic or pharmacological interruption of RAGE signaling affected tumor progression and metastasis. However, no studies have dissected the role of RAGE in tumor growth from the metastatic cascade. Here, we show for the first time in multiple metastatic breast cancer models that targeting RAGE impairs BC metastasis. Methods: We tested the anti-metastatic effect of RAGE in vitro using the RAGE inhibitor FPS-ZM1 or RAGE shRNA knockdown in cell invasion, proliferation, migration and sphere formation assays (with 4T1, Py8119 and E0771 mouse BC cells). For in vivo assays we used orthotopic BC models (4T1/BALB/c and E0771 & Py8119/C57BL6) and experimental metastasis assays (tail vein injection of 4T1/BALB/c and Py8119/C57BL6). To target RAGE, we used genetic (shRNA in 4T1 cells and RAGE knockout in C57BL6 mice) and pharmacological approaches (I.P. injection of FPS-ZM1). To investigate the synergistic effects of RAGE inhibition on progression and metastasis, we tested combination therapy of low-dose doxorubicin and FPS-ZM1. Results: Inhibition of RAGE with FPS-ZM1 (1-5uM) impaired tumor cell invasion of 4T1, E0771 and Py8119 cells. Similarly, in spheroid assays, treatment of cells with FPS-ZM1 resulted in fewer and smaller colonies. However, FPS-ZM1 treatment did not affect cell proliferation. In vivo studies revealed that FPS-ZM1 (1mg/kg) has a modest effect on tumor growth in 4T1/BALB/c injected mice but displayed a dramatic inhibitory effect on metastasis to the lungs. In experimental metastasis assays, tail-vein injection of 4T1 cells in BALB/c mice demonstrated that FPS-ZM1 treatment strongly impaired metastatic disease in mice compared to controls. To dissect the genetic role of RAGE in the tumor versus host, we test the effect of RAGE knockdown in 4T1 cells in experimental metastasis assays. RAGE shRNA impaired metastasis to the lungs, albeit to a lower degree seen with the RAGE inhibitor. To test the role of the host, we injected Py8119 cells into wild-type and RAGE knockout (RKO) mice. RKO mice displayed fewer metastatic burden compared to wild-type mice. Finally, in our combination treatment experiments, treatment of 4T1-injected BALB/c mice with Doxorubicin and FPS-ZM1 (alone and in combination), demonstrated that drug combination was more effective in inhibiting lung metastasis than either reagent alone. We are currently assessing how RAGE mechanistically drives these metastatic changes. Conclusion: Our data strongly suggests RAGE plays an important role in breast cancer metastasis, with less of an effect on tumor growth. Ongoing studies in our lab are testing which stage of the metastatic cascade RAGE is involved in, and the underlying mechanisms driving these processes. In conclusion, the use of RAGE inhibitors could represent a novel therapeutic approach for metastatic breast cancer. Citation Format: Gyong Ha Hwang, Melinda Magna, Barbara Mera, Toni Yeasky, Taekyoung Kwak, Lucas Outcault, Masaru Takabatake, Thuy-Mai Le, Marc E. Lippman, Barry I. Hudson. Targeting RAGE inhibits breast cancer invasion and metastasis [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 P3-01-11.

Rotator cuff (RC) disease, defined as any pathological state of the rotator cuff, is one of the most common shoulder conditions worldwide. It accounts for 70% of shoulder pain and dysfunction in adults and is the third most prevalent musculoskeletal disorder. Currently, the main issue with rotator cuff disease is that surgery represents the most common treatment performed. However, rotator cuff surgeries have a high failure rate positively correlated with the severity of the tear, and a high re-tear rate. This review will focus on the current research perspectives of rotator cuff repairs as well as new advances in the field. Current research is shifting its focus to target the healing and tendon repair process in an aim to decrease the failure rates. The bulk of research right now is within biologic methods based on growth factors, repair scaffolds, and stem cells that promote healing. Among this, researchers are continuously trying to improve surgical techniques. The complement of both methods should pave the way for much more effective, longer-lasting rotator cuff repairs.

Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic cancer subtype, which is generally untreatable once it metastasizes. We hypothesized that interfering with the Receptor for Advanced Glycation End-products (RAGE) signaling with the small molecule RAGE inhibitors (TTP488/Azeliragon and FPS-ZM1) would impair TNBC metastasis and impair fundamental mechanisms underlying tumor progression and metastasis. Both TTP488 and FPS-ZM1 impaired spontaneous and experimental metastasis of TNBC models, with TTP488 reducing metastasis to a greater degree than FPS-ZM1. Transcriptomic analysis of primary xenograft tumor and metastatic tissue revealed high concordance in gene and protein changes with both drugs, with TTP488 showing greater potency against metastatic driver pathways. Phenotypic validation of transcriptomic analysis by functional cell assays revealed that RAGE inhibition impaired TNBC cell adhesion to multiple extracellular matrix proteins (including collagens, laminins, and fibronectin), migration, and invasion. Neither RAGE inhibitor impaired cellular viability, proliferation, or cell cycle in vitro. Proteomic analysis of serum from tumor-bearing mice revealed RAGE inhibition affected metastatic driver mechanisms, including multiple cytokines and growth factors. Further mechanistic studies by phospho-proteomic analysis of tumors revealed RAGE inhibition led to decreased signaling through critical BC metastatic driver mechanisms, including Pyk2, STAT3, and Akt. These results show that TTP488 impairs metastasis of TNBC and further clarifies the signaling and cellular mechanisms through which RAGE mediates metastasis. Importantly, as TTP488 displays a favorable safety profile in human studies, our study provides the rationale for evaluating TTP488 in clinical trials to treat or prevent metastatic TNBC.