Therapeutics
Abstract
Aromatase inhibitors (AIs) reduce breast cancer recurrence and prolong survival, but up to 30% of patients exhibit recurrence. Using a genome-wide association study of patients entered on MA.27, a phase III randomized trial of anastrozole vs exemestane, we identified a SNP in CUB And Sushi Multiple Domains 1 (CSMD1) associated with breast cancer free interval, with the variant allele associated with fewer distant recurrences. Mechanistically, CSMD1 regulates CYP19 expression in a SNP-, and drug-dependent fashion and this regulation is different among three AIs, anastrozole, exemestane, and letrozole. Overexpression of CSMD1 sensitized AI-resistant cells to anastrozole but not to the other two AIs. The SNP in CSMD1 that was associated with increased CSMD1 and CYP19 expression levels increased anastrozole sensitivity, but not letrozole or exemestane sensitivity. Anastrozole degrades estrogen receptor α (ERα), especially in the presence of estradiol (E2). ER positive breast cancer organoids and AI- or fulvestrant-resistant breast cancer cells were more sensitive to anastrozole plus E2 than to AI alone. Our findings suggest that the CSMD1 SNP might help to predict AI response and anastrozole plus E2 serves as a potential new therapeutic strategy for patients with AI- or fulvestrant-resistant breast cancers.
Authors
Junmei Cairns, James N. Ingle, Tanda T. M. Dudenkov, Krishna R. Kalari, Erin E. Carlson, Jie Na, Aman U. Buzdar, Mark E. Robson, Matthew J. Ellis, Paul E. Goss, Lois E. Shepherd, Barbara Goodnature, Matthew P. Goetz, Richard M. Weinshilboum, Hu Li, Mehrab Ghanat Bari, Liewei Wang
Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel tick-borne bunyavirus that recently emerged in East Asian countries. SFTS is characterized by high fever, thrombocytopenia, leukopenia, multiorgan failure, and hemorrhage with case fatality rates of 6.3% to 30%. Neither antivirals nor vaccines are available at present. We previously demonstrated that neutralizing antibodies specific for SFTSV glycoprotein (Gn) played a vital role in the survival of patients with SFTS. Nanobodies from camels present unique properties, such as thermostability, high affinity, and low immunogenicity. In the current study, mammalian expressed SFTSV Gn was used to immunize a camel, and functional nanobodies were isolated from the B cell nanobody library constructed from the immunized animal. Clone SNB02 was selected for in-depth analysis for its inhibition of SFTSV replication both in vitro and in vivo. We showed that SNB02 potently inhibited SFTSV infection and prevented thrombocytopenia in a humanized mouse model and is a potential candidate for therapeutics.
Authors
Xilin Wu, Yanlei Li, Bilian Huang, Xiaohua Ma, Linjing Zhu, Nan Zheng, Shijie Xu, Waqas Nawaz, Changping Xu, Zhiwei Wu
Abstract
De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis. In humans with lipodystrophy, reduced adipose tissue causes lower plasma leptin, insulin resistance, dyslipidemia and ectopic triglyceride (TG) accumulation. We hypothesized that recombinant leptin (metreleptin) for 6 months in 11 patients with lipodystrophy would reduce DNL by decreasing insulin resistance and glycemia, thus reducing circulating and hepatic-TG. The percentage of TG-rich lipoprotein particle (TRLP)-TG derived from DNL (%DNL) was measured by deuterium incorporation from body water into palmitate. At baseline, DNL was elevated with levels similar to levels previously shown in obesity-associated nonalcoholic fatty liver disease (NAFLD). After metreleptin, DNL decreased into the normal range. Similarly, absolute DNL (TRLP-TG x % DNL) decreased by 88% to near-normal levels. Metreleptin improved peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) and lowered HbA1c and hepatic-TG. Both before and after metreleptin, DNL positively correlated with insulin resistance, insulin doses, and hepatic-TG, supporting the hypothesis that hyperinsulinemia stimulates DNL and that elevated DNL is integral to the pathogenesis of lipodystrophy-associated NAFLD.These data suggest that leptin-mediated improvement in insulin sensitivity increases clearance of blood glucose by peripheral tissues, reduces hepatic carbohydrate flux, and lowers insulinemia, resulting in DNL reductions, and improvements in hepatic steatosis and dyslipidemia.
Authors
Annah P. Baykal, Elizabeth J. Parks, Robert Shamburek, Majid M. Syed-Abdul, Shaji K. Chacko, Elaine Cochran, Megan Startzell, Ahmed M. Gharib, Ronald Ouwerkerk, Khaled Z. Abd-Elmoniem, Peter J. Walter, Mary Walter, Ranganath Muniyappa, Stephanie T. Chung, Rebecca J. Brown
Abstract
Off-tumor targeting of human antigens is difficult to predict in preclinical animal studies and can lead to serious adverse effects in patients. To address this, we developed a mouse model with stable and tunable human HER2 (hHER2) expression on normal hepatic tissue and compared toxicity between affinity-tuned HER2 CAR T cells (CARTs). In mice with hHER2-high livers, both the high-affinity (HA) and low-affinity (LA) CARTs caused lethal liver damage due to immunotoxicity. Mice with hHER2-low livers, LA-CARTs exhibited less liver damage and lower systemic levels of IFN-γ than HA-CARTs. We then compared affinity-tuned CARTs for their ability to control a hHER2-positive tumor xenograft in our model. Surprisingly, the LA-CARTs outperformed the HA-CARTs with superior antitumor efficacy in vivo. We hypothesized that this was due in part to T cell trafficking differences between LA and HA-CARTs and found that the LA-CARTs migrated out of the liver and infiltrated the tumor sooner than the HA-CARTs. These findings highlight the importance of T cell targeting in reducing toxicity of normal tissue and also in preventing off-tumor sequestration of CARTs, which reduces their therapeutic potency. Our model may be useful to evaluate various CARTs that have conditional expression of more than one scFv.
Authors
Mauro Castellarin, Caroline Sands, Tong Da, John Scholler, Kathleen Graham, Elizabeth Buza, Joseph A. Fraietta, Yangbing Zhao, Carl H. June
Abstract
Musculoskeletal disorders represent the 3rd greatest burden on health in the developed world. Osteoarthritis is the single greatest cause of chronic pain, has no cure, and affects 8.5 and 27 million in the UK and US respectively. Osteoarthritis commonly occurs after joint injury, particularly affecting younger patients. Painful joints are often treated with injections of steroid or hyaluronic acid (HA), but treatments to prevent subsequent joint degeneration remain elusive. In animals, joint injury increases glutamate release into the joint, acting on nerves to cause pain, and joint tissues to cause inflammation and degeneration. This study investigated synovial fluid glutamate concentrations and glutamate receptor (GluR) expression in injured human joints and compared efficacy of GluR antagonists with current treatments in a mouse model of injury-induced osteoarthritis (ACL rupture). GluRs were expressed in ligament and meniscus after knee injury and synovial fluid glutamate concentrations ranged from 19–129 µM. Intra-articular injection of NBQX (GluR antagonist), administered at the time of injury, substantially reduced swelling and degeneration in the mouse ACL rupture model. HA had no effect and depo-medrone reduced swelling for 1 day, but increased degeneration by 50%. Intra-articular administration of NBQX was both symptom and disease modifying to a greater extent than current treatments. There is an opportunity for repurposing related drugs, developed for CNS disorders, with proven safety in man, to prevent injury-induced osteoarthritis. This could quickly reduce the substantial burden associated with osteoarthritis.
Authors
Cleo S. Bonnet, Sophie J. Gilbert, Emma J. Blain, Anwen S. Williams, Deborah J. Mason
Abstract
Regulatory T cells (Tregs) play essential roles in maintaining immunological self-tolerance and preventing autoimmunity. The adoptive transfer of antigen-specific Tregs has been expected to be a potent therapeutic method for autoimmune diseases, severe allergy, and rejection in organ transplantation. However, effective Treg therapy has not yet been established because of the difficulty in preparing a limited number of antigen-specific Tregs. Chimeric antigen receptor (CAR) T cells have been shown to be a powerful therapeutic method for treating B cell lymphomas, but application of CAR to Treg-mediated therapy has not yet been established. Here, we generated CD19-targeted CAR (CD19-CAR) Tregs from human peripheral blood mononuclear cells (hPBMCs) and optimized the fraction of the Treg source as CD4+CD25+CD127lowCD45RA+CD45RO–. CD19-CAR Tregs could be expanded in vitro while maintaining Treg properties, including a high expression of the latent form of TGF-β. CD19-CAR Tregs suppressed IgG antibody production from primary B cell differentiation in vitro via a TGF-β-dependent mechanism. Unlike conventional CD19-CAR CD8+ T cells, CD19-CAR Tregs suppressed antibody production in immunodeficient mice that were reconstituted with hPBMCs with reducing the risk of graft-versus-host disease. Therefore, the adoptive transfer of CD19-CAR Tregs may provide a novel therapeutic method for treating autoantibody-mediated autoimmune diseases.
Authors
Yuki Imura, Makoto Ando, Taisuke Kondo, Minako Ito, Akihiko Yoshimura
Abstract
The mortality of patients suffering from acute myocardial infarction (AMI) is linearly related to the infarct size. As regeneration of cardiomyocytes from cardiac progenitor cells is minimal in the mammalian adult heart, we have explored a new therapeutic approach which leverages the capacity of nanomaterials to release chemicals over time to promote myocardial protection and infarct size reduction. Initial screening identified two chemicals, FGF1 and CHIR99021 (a Wnt1 agonist/GSK-3ß antagonist) which synergistically enhance cardiomyocyte cell cycle in vitro. Poly-lactic-co-glycolic acid (PLGA) nanoparticles (NP) formulated with CHIR99021 and FGF1 (CHIR+FGF1-NPs) provided an effective slow release system for up to 4 weeks. Intramyocardial injection of CHIR+FGF1-NPs enabled myocardial protection via reducing infarct size by 20% to 30% in mouse or pig models of postinfarction LV remodeling. This LV structural improvement was accompanied by a significant preservation of cardiac contractile function. Further investigation revealed that CHIR+FGF1-NPs resulted in a significant reduction of cardiomyocyte apoptosis and increase of angiogenesis. Thus, using a combination of chemicals and a NP-based prolonged release system that work synergistically, this study demonstrates a novel therapy for LV infarct size reduction in hearts with acute myocardial infarction.
Authors
Chengming Fan, Yasin Oduk, Meng Zhao, Xi Lou, Yawen Tang, Danielle Pretorius, Mani T. Valarmathi, Gregory P. Walcott, Jingfu Yang, Philippe Menasche, Prasanna Krishnamurthy, Wuqiang Zhu, Jianyi Zhang
Abstract
The SIRPα-CD47 interaction provides a macrophage immune checkpoint pathway that plays a critical role in cancer immune evasion across multiple cancers. Here, we report the engineering of a humanized anti-SIRPα monoclonal antibody (1H9) for antibody target cancer therapy. 1H9 has broad activity across a wide range of SIRPα variants. Binding of 1H9 to SIRPα blocks its interaction with CD47, thereby promoting macrophage-mediated phagocytosis of cancer cells. Pre-clinical studies in vitro and in vivo demonstrate that 1H9 synergizes with other therapeutic antibodies to promote phagocytosis of tumor cells and inhibit tumor growth in both syngeneic and xenograft tumor models, leading to survival benefit. Thus, 1H9 can potentially act as a universal agent to enhance therapeutic efficacy when used in combination with most tumor-targeting antibodies. We report for the first time, a comparison of anti-SIRPα and anti-CD47 antibodies in CD47/SIRPα double humanized mice, and found that 1H9 exhibits a substantially reduced antigen-sink effect due to the limited tissue distribution of SIRPα expression. Toxicokinetic studies in non-human primates show that 1H9 is well tolerated with no treatment-related adverse effects noted. These data highlight the clinical potential of 1H9 as a pan-therapeutic with the desired properties when used in combination with tumor-targeting antibodies.
Authors
Jie Liu, Seethu Xavy, Shirley Mihardja, Sharline Chen, Kavitha Sompalli, Dongdong Feng, Timothy S. Choi, Balaji Agoram, Ravindra Majeti, Irving L. Weissman, Jens-Peter Volkmer
Abstract
Colitis is associated with the development of colorectal cancer (CRC) by largely undefined mechanisms that are critical for understanding the link between inflammation and cancer. Intestinal stem cells (ISCs) marked by LGR5 expression are of importance in both the inflammatory response to colitis and progression to colitis-associated colon cancer (CACC). Here, we report in human MUC1-transgenic mouse models of CACC that targeting the MUC1-C oncogenic protein, which is upregulated in inflammation, suppresses the (i) Lgr5+ ISC population, (ii) induction of Myc and core pluripotency stem cell factors, and (iii) severity and progression of colitis to dysplasia and cancer. By extension to human colon cancer cells, we demonstrate that MUC1-C drives MYC, forms a complex with MYC on the LGR5 promoter and activates LGR5 expression. We also show in CRC cells that MUC1-C induces the cancer stem cell (CSC) markers (BMI1, ALDH1, FOXA1, LIN28B) and the OCT4, SOX2 and NANOG pluripotency factors. Consistent with conferring the CSC state, targeting MUC1-C suppresses the capacity of CRC cells to promote wound healing, invasion, self-renewal and tumorigenicity. In analysis of human tissues, MUC1 expression associates with activation of inflammatory pathways, development of colitis and aggressiveness of CRCs. These results collectively indicate that MUC1-C is of importance for integrating stemness and pluripotency in colitis and CRC. Of clinical relevance, the findings further indicate that MUC1-C represents a previously unrecognized target that is druggable for treating progression of colitis and CRC.
Authors
Wei Li, Ning Zhang, Caining Jin, Mark D. Long, Hasan Rajabi, Yota Yasumizu, Atsushi Fushimi, Nami Yamashita, Masayuki Hagiwara, Rongbin Zheng, Jin Wang, Ling Kui, Harpal Singh, Surender Kharbanda, Qiang Hu, Song Liu, Donald W. Kufe
Abstract
Autosomal co-dominant genetic disorder alpha-1 antitrypsin (AAT) deficiency (AATD) causes pulmonary and liver disease. Individuals homozygous for the mutant Z allele accumulate polymers of Z-AAT protein in hepatocytes, where AAT is primarily produced. This accumulation causes endoplasmic reticulum (ER) stress, oxidative stress, damage to mitochondria and inflammation, leading to fibrosis, cirrhosis and hepatocellular carcinoma. The magnitude of AAT reduction and duration of response from first generation intravenously-administered RNA interference (RNAi) therapeutic ARC-AAT and then with next generation subcutaneously-administered ARO-AAT were assessed by measuring AAT protein in serum of the PiZ transgenic mouse model and human volunteers. The impact of Z-AAT reduction by RNAi on liver disease phenotypes was evaluated in PiZ mice by measuring polymeric Z-AAT in the liver; expression of genes associated with fibrosis, autophagy, apoptosis and redox regulation; inflammation; Z-AAT globule parameters; and tumor formation. Ultrastructure of the ER, mitochondria and autophagosomes in hepatocytes were evaluated by electron microscopy. In mice, sustained RNAi treatment reduced hepatic Z-AAT polymer, restored ER and mitochondrial health, normalized expression of disease-associated genes, reduced inflammation and prevented tumor formation. RNAi therapy holds promise for the treatment of patients with AATD-associated liver disease. ARO-AAT is currently in Phase 2/3 clinical trials.
Authors
Christine I. Wooddell, Keith Blomenkamp, Ryan M. Peterson, Vladimir M. Subbotin, Christian Schwabe, James Hamilton, Qili Chu, Dawn R. Christianson, Julia O. Hegge, John Kolbe, Holly L. Hamilton, Maria F. Branca-Afrazi, Bruce D. Given, David L. Lewis, Edward Gane, Steven B. Kanner, Jeffrey H. Teckman
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