Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic

Chin, Emily; Yu, Chenguang; Vartabedian, Vincent F.; Jia, Ying; Kumar, M N Satish; Gamo, Ana M.; Vernier, William F.; Ali, Sabrina H.; Kissai, Mildred; Lazar, Daniel C.; Nguyen, Nhan; Pereira, Laura E.; Benish, Brent; Woods, Ashley K.; Joseph, Sean B.; Chu, Alan; Johnson, Kristen A.; Sander, Philipp; Martínez‐Peña, Francisco; Hampton, Eric; Young, Travis S.; Wolan, Dennis W.; Chatterjee, Arnab K.; Schultz, Peter G.; Petrassi, H. Michael; Teijaro, John R.; Lairson, Luke L.

doi:10.1126/science.abb4255

Cited by 323 publications

(261 citation statements)

References 34 publications

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“…As a consequence of genomic insults occurring early in the course of oncogenesis, DNA fragments translocate to the cytoplasm, providing a cellular ''danger signal'' (Dhanwani et al, 2018;Paludan and Bowie, 2013;Won and Bakhoum, 2020). Cytoplasmic DNA sensing and downstream response are critical for anticancer immune responses and have generated excitement as a potential therapeutic opportunity (Chin et al, 2020;Pan et al, 2020). The cytoplasmic DNA sensor is now understood to be a condensate that forms in response to this cellular stress.…”

Section: Revisiting Mechanisms In Common Oncogenic Eventsmentioning

confidence: 99%

Biomolecular Condensates and Cancer

2021

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Section: Revisiting Mechanisms In Common Oncogenic Eventsmentioning

confidence: 99%

Biomolecular Condensates and Cancer

2021

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“…This work has demonstrated that intratumoral activation of the proinflammatory STING pathway by PARP inhibitors is amplified by synthetic cyclic dinucleotide agonists of STING, leading to robust and durable anti-tumor immune responses in BRCA1-mutant TNBC models. It will be important to extend these findings to other tumor models and to determine whether similar results can be achieved with systemic agonists of STING, currently under development (19,20). In conclusion, the potent preclinical therapeutic efficacy of combined PARP inhibition and STING agonism warrants further development of this regimen as a treatment for BRCA-associated TNBC.…”

Section: Resultsmentioning

confidence: 89%

STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition inBRCA-associated breast cancer

Pantelidou

Jadhav

Kothari

et al. 2021

Preprint

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Poly (ADP-ribose) polymerase (PARP) inhibitors exert their efficacy by inducing synthetic lethal effects, as well as cGAS/STING-mediated immune responses in BRCA- and other homologous recombination repair-deficient cancer cells. Here we investigated whether the immunologic and therapeutic effects of PARP inhibition in BRCA-deficient breast cancer models could be augmented by synthetic cyclic dinucleotide agonists of STING. Combined PARP inhibition and STING agonism induced a greater degree of STING pathway activation and proinflammatory cytokine production compared to monotherapies in BRCA1-deficient human and mouse triplenegative breast cancer cell lines. In a mouse model of BRCA1-deficient TNBC, the combination also induced an improved immune response compared to either monotherapy alone, evidenced by a greater degree of cytotoxic T cell recruitment and activation, and enhanced dendritic cell activation and antigen presentation. Nanostring mRNA analysis indicated that combinatorial effects were the result of augmented interferon signaling and antigen processing, as well as of heightened leukocyte and dendritic cell functions. Finally, the combination markedly improved anti-tumor efficacy in vivo compared to monotherapy treatment, with evidence of complete tumor clearance and prolongation of survival. These results support the development of combined PARP inhibition and STING agonism in BRCA-associated breast cancer.

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“…Recent studies reported by Pan et al 138 . and Chin et al 139 . have demonstrated promising results in preclinical models.…”

Section: Targeting the Tmementioning

confidence: 96%

Therapeutic strategies to remodel immunologically cold tumors

Wang

Desai

et al. 2020

Clin & Trans Imm

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Immune checkpoint inhibitors (ICIs) induce a durable response in a wide range of tumor types, but only a minority of patients outside these ‘responsive’ tumor types respond, with some totally resistant. The primary predictor of intrinsic immune resistance to ICIs is the complete or near‐complete absence of lymphocytes from the tumor, so‐called immunologically cold tumors. Here, we propose two broad approaches to convert ‘cold’ tumors into ‘hot’ tumors. The first is to induce immunogenic tumor cell death, through the use of oncolytic viruses or bacteria, conventional cancer therapies (e.g. chemotherapy or radiation therapy) or small molecule drugs. The second approach is to target the tumor microenvironment, and covers diverse options such as depleting immune suppressive cells; inhibiting transforming growth factor‐beta; remodelling the tumor vasculature or hypoxic environment; strengthening the infiltration and activation of antigen‐presenting cells and/or effector T cells in the tumor microenvironment with immune modulators; and enhancing immunogenicity through personalised cancer vaccines. Strategies that successfully modify cold tumors to overcome their resistance to ICIs represent mechanistically driven approaches that will ultimately result in rational combination therapies to extend the clinical benefits of immunotherapy to a broader cancer cohort.

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Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic

Cited by 323 publications

References 34 publications

Biomolecular Condensates and Cancer

Biomolecular Condensates and Cancer

STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition inBRCA-associated breast cancer

Therapeutic strategies to remodel immunologically cold tumors

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