Several poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved by FDA treat cancer with BRCA mutations. BRCA mutation is considered to fuel PARPi killing effect by inducing apoptosis. However, resistance to PARPi is frequently observed in clinic due to incomplete understanding on the molecular basis of PARPi function and lack of good markers to predict response in addition to BRCA mutations. Here we show that gasdermin C (GSDMC) sensitized tumor cells to PARPi in vitro and in immunocompetent mice and caused durable tumor regression in an immune-dependent manner. High expression level of GSDMC predicted better response to PARPi treatment in triple-negative breast cancer (TNBC) patients. PARPi treatment triggered GSDMC/caspase-8-mediated cancer cell pyroptosis (CCP) that enhanced PARPi killing of tumor cells. GSDMC-mediated CCP increased memory CD8+ T cell population in lymph node (LN), spleen, tumor, and thus promoted cytotoxic CD8+ T cell infiltration in tumor microenvironment. T cell-derived granzyme B (GZMB) activated caspase-6, which subsequently cleaved GSDMC to induce pyroptosis. Interestingly, IFN-γ induced GSDMC expression, which in turn enhanced the cytotoxicity of PARPi and T cell. Importantly, GSDMC promoted tumor clearance independent of BRCA deficiency in multiple cancer types with PARPi treatment. This study identifies a general marker and target for PARPi therapy and offers new insights into the mechanism of PARPi function.
Shuanglian Wang, Chiung-Wen Chang, Juan Huang, Shan Zeng, Xin Zhang, Mien-Chie Hung, Junwei Hou
Garth T. Whiteside, Donald J. Kyle, Ram P. Kapil, Alessandra Cipriano, Ellie He, Mingyan Zhou, Manjunath S. Shet, Michele Hummel, Terri Knappenberger, Kazuya Fukumura, Yoshiyuki Matsuo, Masahiro Uehira, Shuichi Hiroyama, Nozomi Takai, Sandra K. Willsie, Stephen C. Harris
Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-alpha (G6Pase-α, encoded by G6PC), primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves the life expectancy, patients still suffer from intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities such as adeno-associated virus and mRNA with lipid nanoparticles are under development for GSD1a, but potentially require complicated glycemic management throughout life. Here, we present a oligonucleotide-based therapy to produce intact G6Pase-α from a pathogenic human variant, G6PC c.648G>T, the most prevalent variant in East Asia causing aberrant splicing of G6PC. DS-4108b, a splice-switching oligonucleotide, was designed to correct this aberrant splicing, especially in liver. A generated mouse strain with homozygous knock-in of this variant well reflected the pathophysiology of GSD1a patients. DS-4108b recovered hepatic G6Pase activity through splicing correction and prevented hypoglycemia and various hepatic abnormalities in the mice. Moreover, DS-4108b exhibited long-lasting efficacy for more than 12 weeks in the mice with a single dose and favorable pharmacokinetics and tolerability in mice and monkeys. Taking these findings together, this oligonucleotide-based therapy could provide a sustainable and curative therapeutic option under easy disease management for GSD1a patients with G6PC c.648G>T.
Kentaro Ito, Go Tajima, Chikako Kamisato, Miyuki Tsumura, Mitsuhiro Iwamoto, Yukiko Sekiguchi, Yukinobu Numata, Kyoko Watanabe, Yoshiyuki Yabe, Satomi Kanki, Yusuke Fujieda, Koichi Goto, Yoshitaka Sogawa, Masataka Oitate, Hiroyuki Nagase, Shinnosuke Tsuji, Tomohiro Nishizawa, Masayo Kakuta, Takeshi Masuda, Yoshiyuki Onishi, Makoto Koizumi, Hidefumi Nakamura, Satoshi Okada, Masafumi Matsuo, Kiyosumi Takaishi
Antibody-drug conjugates(ADCs) are promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer(mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross-linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, conferred sensitivity and were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive(ARPC) prostate cancer models, even with low B7H3 levels. Non-ARPC models, which are currently lacking efficacious treatment, demonstrated the highest replication stress and were most sensitive to treatment. In RB1 wild-type ARPC tumors, SLFN11 expression or select DNA repair mutations in SLFN11 non-expressors governed response. Importantly, wild-type TP53 predicted non-responsiveness (7/8 models). Overall, biomarker-focused selection of models led to high efficacy of in vivo treatment. These data enable a paradigm shift to biomarker-driven trial designs for maximizing clinical benefit of ADC therapies.
Supreet Agarwal, Lei Fang, Kerry McGowen, JuanJuan Yin, Joel Bowman, Anson T. Ku, Aian Neil Alilin, Eva Corey, Martine P. Roudier, Lawrence D. True, Ruth F. Dumpit, Ilsa Coleman, John K. Lee, Peter S. Nelson, Brian J. Capaldo, Aida Mariani, Clare E. Hoover, Ilya S. Senatorov, Michael Beshiri, Adam G. Sowalsky, Elaine M. Hurt, Kathleen Kelly
Expansion of CAG and CTG (CWG) triplet repeats causes several inherited neurological diseases. The CWG repeat diseases are thought to involve complex pathogenic mechanisms through expanded CWG repeat-derived RNAs in a non-coding and polypeptides in a coding region, respectively. However, an effective therapeutic approach has not been established for the CWG repeat diseases. Here, we show that a CWG repeat DNA-targeting compound, cyclic pyrrole¬–imidazole polyamide (CWG-cPIP), suppresses the pathogenesis of coding and non-coding CWG repeat diseases. CWG-cPIP binds to the hairpin form of mismatched CWG DNA, interfering with transcription elongation by RNA polymerase through a preferential activity towards repeat-expanded DNA. We found that CWG-cPIP selectively inhibits pathogenic mRNA transcripts from expanded CWG repeats, reducing CUG RNA foci and polyglutamine accumulation in cells from patients with myotonic dystrophy type-1 (DM1) and Huntington’s disease (HD). Treatment with CWG-cPIP ameliorated behavioral deficits in adeno-associated virus-mediated CWG repeat-expressing mice and a genetic mouse model of HD, without cytotoxicity or off-target effects. Together, we present a novel candidate compound that targets expanded CWG repeat DNA independent of its genomic location and reduces both pathogenic RNA and protein levels. CWG-cPIP may be used for the treatment of CWG repeat diseases and for improving clinical outcomes.
Susumu Ikenoshita, Kazuya Matsuo, Yasushi Yabuki, Kosuke Kawakubo, Sefan Asamitsu, Karin Hori, Shingo Usuki, Yuki Hirose, Toshikazu Bando, Kimi Araki, Mitsuharu Ueda, Hiroshi Sugiyama, Norifumi Shioda
Biofilms are structured communities of microbial cells embedded in a self-produced matrix of extracellular polymeric substances. Biofilms are associated with many health issues in humans, including chronic wound infections and tooth decay. Current antimicrobials are often incapable of disrupting the polymeric biofilm matrix and reaching the bacteria within. Alternative approaches are needed. Here, we describe a unique structure of dextran coated gold in a gold cage nanoparticle that enables photoacoustic and photothermal properties for biofilm detection and treatment. Activation of these nanoparticles with a near infrared laser can selectively detect and kill biofilm bacteria with precise spatial control and in a short timeframe. We observe a strong biocidal effect against both Streptococcus mutans and Staphylococcus aureus biofilms in mouse models of oral plaque and wound infections respectively. These effects were over 100 times greater than that seen with chlorhexidine, a conventional antimicrobial agent. Moreover, this approach did not adversely affect surrounding tissues. We conclude that photothermal ablation using theranostic nanoparticles is a rapid, precise, and non-toxic method to detect and treat biofilm-associated infections.
Maryam Hajfathalian, Christiaan R. de Vries, Jessica C. Hsu, Ahmad Amirshaghaghi, Yuxi C. Dong, Zhi Ren, Yuan Liu, Yue Huang, Yong Li, Simon A.B. Knight, Pallavi Jonnalagadda, Aimen Zlitni, Elizabeth A. Grice, Paul L. Bollyky, Hyun Koo, David P. Cormode
The triggering receptor expressed on myeloid cell 1 (TREM1) plays a critical role in development of chronic inflammatory disorders and the inflamed tumor microenvironment (TME) associated with most solid tumors. We examined whether loss of TREM1 signaling can abrogate immunosuppressive TME and enhance cancer immunity. To investigate the therapeutic potential of TREM1 in cancer, we used mice deficient in Trem1 and developed a novel small molecule TREM1 inhibitor, VJDT. We demonstrated that genetic or pharmacological TREM1 silencing significantly delayed tumor growth in murine melanoma (B16F10) and fibrosarcoma (MCA205) models. Single-cell RNA-seq combined with functional assays during TREM1 deficiency revealed decreased immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs) accompanied by expansion in cytotoxic CD8+ T cells and increased PD-1 expression. Furthermore, TREM1 inhibition enhanced antitumorigenic effect of anti-PD-1 treatment in part by limiting MDSC frequency and abrogating T cell exhaustion. In melanoma patient-derived xenograft tumors, treatment with VJDT downregulated key oncogenic signaling pathways involved in cell proliferation, migration, and survival. Our work highlights the role in cancer progression of TREM1 expressed intrinsically in cancer cells and extrinsically in TME. Thus, targeting TREM1 to modify an immunosuppressive TME and improve efficacy of immune checkpoint therapy represents a promising therapeutic approach in cancer.
Ashwin Ajith, Kenza Mamouni, Daniel D. Horuzsko, Abu Musa, Amiran K. Dzutsev, Jennifer R. Fang, Ahmed Chadli, Xingguo Zhu, Iryna Lebedyeva, Giorgio Trinchieri, Anatolij Horuzsko
SARS-CoV-2 infection during pregnancy is associated with severe COVID-19 and adverse fetal outcomes, but the underlying mechanisms remain poorly understood. Moreover, clinical studies assessing therapeutics against SARS-CoV-2 in pregnancy are limited. To address these gaps, we developed a mouse model of SARS-CoV-2 infection during pregnancy. Outbred CD1 mice were infected at embryonic day (E) 6, E10, or E16 with a mouse adapted SARS-CoV-2 (maSCV2) virus. Outcomes were gestational age-dependent, with greater morbidity, reduced anti-viral immunity, greater viral titers, and impaired fetal growth and neurodevelopment occurring with infection at E16 (3rd trimester-equivalent) than with infection at either E6 (1st trimester-equivalent) or E10 (2nd trimester-equivalent). To assess the efficacy of ritonavir-boosted nirmatrelvir (recommended for pregnant individuals with COVID-19), we treated E16-infected dams with mouse equivalent doses of nirmatrelvir and ritonavir. Treatment reduced pulmonary viral titers, decreased maternal morbidity, and prevented offspring growth restriction and neurodevelopmental impairments. Our results highlight that severe COVID-19 during pregnancy and fetal growth restriction are associated with heightened virus replication in maternal lungs. Ritonavir-boosted nirmatrelvir mitigated maternal morbidity along with fetal growth and neurodevelopment restriction after SARS-CoV-2 infection. These findings prompt the need for further consideration of pregnancy in preclinical and clinical studies of therapeutics against viral infections.
Patrick S. Creisher, Jamie L. Perry, Weizhi Zhong, Jun Lei, Kathleen R. Mulka, W. Hurley Ryan, Ruifeng Zhou, Elgin H. Akin, Anguo Liu, Wayne Mitzner, Irina Burd, Andrew Pekosz, Sabra L. Klein
Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, 2 and 4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, pro-inflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production and disruption of the blood-brain barrier integrity in microfluidic-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof-of-principle for a repurposed, ErbB-targeted approach to combat emerging viruses.
Sirle Saul, Marwah Karim, Luca Ghita, Pei-Tzu Huang, Winston Chiu, Verónica Durán, Chieh-Wen Lo, Sathish Kumar, Nishank Bhalla, Pieter Leyssen, Farhang Alem, Niloufar A. Boghdeh, Do HoangNhu Tran, Courtney A. Cohen, Jacquelyn A. Brown, Kathleen E. Huie, Courtney Tindle, Mamdouh Sibai, Chengjin Ye, Ahmed Magdy Khalil, Kevin Chiem, Luis Martinez-Sobrido, John M. Dye, Benjamin A. Pinsky, Pradipta Ghosh, Soumita Das, David E. Solow-Cordero, Jing Jin, John P. Wikswo, Dirk Jochmans, Johan Neyts, Steven De Jonghe, Aarthi Narayanan, Shirit Einav
Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote bronchodilation in asthma, but have limited efficacy. All β2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a β2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of GPCR allosteric ligands, we investigated the impact of Cmpd-6 on β2AR-mediated bronchoprotection. Consistent with our findings using human β2ARs, Cmpd-6 allosterically potentiated β2-agonist binding to, and downstream signaling of, guinea pig β2ARs. In contrast, Cmpd-6 had no such effect on murine β2ARs which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced β2-agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in guinea pig lung slices, but – in line with the binding studies – not in mice. Moreover, Cmpd-6 robustly potentiated β2-agonist-mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced β2-agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of β2AR-selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases.
Seungkirl Ahn, Harm Maarsingh, Julia K.L. Walker, Samuel W. Liu, Akhil Hegde, Hyeje C. Sumajit, Alem W. Kahsai, Robert J. Lefkowitz
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