作者: Chan, Li-Chuan Eric ; Schechter, Emma Y ; Tobias, John W ; Corse, Emily ; Markosyan, Nune ; Stanger, Ben Z ; Arora, Charu ; Liu, Kang ; Smyth, Emer M ; Joshi, Nikhil ; Quinones-Ware, Liz ; FitzGerald, Garret A ; Rodriguez DiBlasi, Varenka ; Hochberg, Joseph E ; Vonderheide, Robert H ; Cheng, Noah ; Kim, Il-Kyu

Tumor cell-derived prostaglandin E2 (PGE2) is a tumor cell-intrinsic factor that supports immunosuppression in the tumor microenvironment (TME) by acting on the immune cells, but the impact of PGE2 signaling in tumor cells on the immunosuppressive TME is unclear. We demonstrate that deleting the PGE2 synthesis enzyme or disrupting autocrine PGE2 signaling through EP4 receptors on tumor cells reverses the T cell-low, myeloid cell-rich TME, activates T cells, and suppresses tumor growth. Knockout (KO) of Ptges (the gene encoding the PGE2 synthesis enzyme mPGES-1) or the EP4 receptor gene (Ptger4) in KPCY (KrasG12D P53R172H Yfp CrePdx) pancreatic tumor cells abolished growth of implanted tumors in a T cell-dependent manner. Blockade of the EP4 receptor in combination with immunotherapy, but not immunotherapy alone, induced complete tumor regressions and immunological memory. Mechanistically, Ptges- and Ptger4-KO tumor cells exhibited altered T and myeloid cell attractant chemokines, became more susceptible to TNF-α-induced killing, and exhibited reduced adenosine synthesis. In hosts treated with an adenosine deaminase inhibitor, Ptger4-KO tumor cells accumulated adenosine and gave rise to tumors. These studies reveal an unexpected finding - a nonredundant role for the autocrine mPGES-1/PGE2/EP4 signaling axis in pancreatic cancer cells, further nominating mPGES-1 inhibition and EP4 blockade as immune-sensitizing therapy in cancer.

2024-09-01·Expert Opinion on Therapeutic Targets

Combined cancer immunotherapy based on targeting adenosine pathway and PD-1/PDL-1 axis

Review

作者: Zarei, Asieh ; Moghimi, Ata ; Jalali, Pooya ; Jadidi-Niaragh, Farhad ; Gholamin, Sharareh ; Salehi, Zahra ; Fathi, Mehrdad

INTRODUCTIONCancer immunotherapy has revolutionized the field of oncology, offering new hope to patients with advanced malignancies. Tumor-induced immunosuppression limits the effectiveness of current immunotherapeutic strategies, such as PD-1/PDL-1 checkpoint inhibitors. Adenosine, a purine nucleoside molecule, is crucial to this immunosuppression because it stops T cells from activating and helps regulatory T cells grow. Targeting the adenosine pathway and blocking PD-1/PDL-1 is a potential way to boost the immune system's response to tumors.AREAS COVEREDThis review discusses the current understanding of the adenosine pathway in tumor immunology and the preclinical and clinical data supporting the combination of adenosine pathway inhibitors with PD-1/PDL-1 blockade. We also discuss the challenges and future directions for developing combination immunotherapy targeting the adenosine pathway and the PD-1/PDL-1 axis for cancer treatment.EXPERT OPINIONThe fact that the adenosine signaling pathway controls many immune system processes suggests that it has a wide range of therapeutic uses. Within the next five years, there will be tremendous progress in this area, and the standard of care for treating malignant tumors will have switched from point-to-point therapy to the integration of immunological networks comprised of multiple signaling pathways, like the adenosine axis.

2024-08-01·Nagoya journal of medical science

Adenosine triphosphate release inhibitors targeting pannexin1 improve recovery after spinal cord injury.

Article

作者: Ito, Sadayuki ; Morishita, Kazuaki ; Imagama, Shiro ; Nakashima, Hiroaki ; Miyairi, Yuichi ; Segi, Naoki ; Morita, Yoshinori ; Machino, Masaaki

Traumatic spinal cord injury is characterized by immediate and irreversible tissue loss at the lesion site and secondary tissue damage. Secondary injuries should, in principle, be preventable, although no effective treatment options currently exist for patients with acute spinal cord injury. Traumatized tissues release excessive amounts of adenosine triphosphate and activate the P2X purinoceptor 7/pannexin1 complex, which is associated with secondary injury. We investigated the neuroprotective effects of the blue dye Brilliant Blue FCF, a selective inhibitor of P2X purinoceptor 7/pannexin1 that is approved for use as a food coloring, by comparing it with Brilliant Blue G, a P2X7 purinoceptor antagonist, and carbenoxolone, which attenuates P2X purinoceptor 7/pannexin1 function, in a rat spinal cord injury model. Brilliant Blue FCF administered early after spinal cord injury reduced spinal cord anatomical damage and improved motor recovery without apparent toxicity. Brilliant Blue G had the highest effect on this neurological recovery, with Brilliant Blue FCF and carbenoxolone having comparable improvement. Furthermore, Brilliant Blue FCF administration reduced local astrocytic and microglial activation and neutrophil infiltration, and no differences in these histological effects were observed between compounds. Thus, Brilliant Blue FCF protects spinal cord neurons after spinal cord injury and suppresses local inflammatory responses as well as Brilliant Blue G and carbenoxolone.

项与 Adenosine inhibitors(Texas A&M University) 相关的新闻（医药）

2024-08-13

·GlobeNewswire-Health Care

Portage Biotech Announces 1-for-20 Reverse Stock Split

WESTPORT, Conn., Aug. 13, 2024 (GLOBE NEWSWIRE) -- Portage Biotech Inc. (“Portage” or the “Company”) (NASDAQ: PRTG), a clinical-stage immuno-oncology company with a portfolio of novel multi-targeted therapies for use as monotherapy and in combination, today announced that the Company’s Board of Directors approved a reverse stock split of its ordinary shares at a ratio of 1-for-20. Beginning with the opening of trading on August 15, 2024, Portage’s ordinary shares are expected to begin trading on The Nasdaq Capital Market on a split-adjusted basis under the existing trading symbol “PRTG” and new CUSIP number G7185A136. The reverse stock split is being implemented to increase the per share trading price of the Company’s ordinary shares for the purpose of ensuring a share price high enough to comply with the minimum $1.00 bid price requirement for continued listing on The Nasdaq Capital Market. As a result of the reverse stock split, every twenty (20) pre-split ordinary shares will be converted into one (1) post-split ordinary share. Any fractional shares resulting from the reverse stock split will be rounded up to the nearest whole post-split ordinary share. The reverse stock split affects all shareholders uniformly and will not alter any shareholder’s percentage interest in the Company’s ordinary shares, except for adjustments that may result from the treatment of fractional shares. All outstanding options and warrants entitling their holders to purchase the Company’s ordinary shares will be adjusted as a result of the reverse stock split, in accordance with the terms of each such security. In addition, the number of ordinary shares reserved for future issuance pursuant to the Company’s equity incentive plans will also be appropriately adjusted. The number of authorized ordinary shares will not be proportionately reduced because the Company has an unlimited number of authorized ordinary shares available for issuance, as permitted under the laws of the British Virgin Islands. Portage’s transfer agent, TSX Trust Company, which is also acting as the exchange agent for the reverse stock split, will provide instructions to shareholders regarding the process for exchanging any share certificates. About Portage Biotech Inc. Portage is a clinical-stage immuno-oncology company advancing multi-targeted therapies to extend survival and significantly improve the lives of patients with cancer. The Company has made the decision to discontinue its sponsored trial for its the invariant natural killer T-cell (iNKT) program and pause patient enrollment to its sponsored adenosine trial program (ADPORT-601 trial) for its potentially best-in-class adenosine antagonists PORT-6 (adenosine 2A inhibitor) and PORT-7 (adenosine 2B inhibitor). The Company is exploring strategic alternatives, which may include finding a partner for one or more of its assets, a sale of the company, a merger, restructurings, both in and out of court, a company wind down, further financing efforts or other strategic action. For more information, please visit www.portagebiotech.com, follow us on Twitter at @PortageBiotech or find us on LinkedIn at Portage Biotech Inc. Forward-Looking Statements All statements in this news release, other than statements of historical facts, including without limitation, statements regarding about the Company’s information that are forward-looking in nature and, business strategy, plans and objectives of management for future operations and those statements preceded by, followed by or that otherwise include the words "believe," "expects," "anticipates," "intends," "estimates," “will,” “may,” “plan,” “potential,” “continue,” or similar expressions or variations on such expressions are forward-looking statements. For example, statements regarding the reverse stock split and the timing thereof and expectations related thereto, and compliance with the minimum bid price requirement are forward-looking statements. The Company may not actually achieve the plans, intentions or expectations disclosed in the forward-looking statements and you should not place undue reliance on the forward-looking statements. These forward-looking statements involve risks and uncertainties that could cause the Company’s actual results to differ materially from the results described in or implied by the forward-looking statements. Factors that may cause the Company’s actual results to differ materially from those expressed or implied in the forward-looking statements in this news release are described in “Item 3 - Key Information-Risk Factors” in the Company’s Annual Report on Form 20-F for the year ended March 31, 2023. Although the Company believes that the expectations reflected in these forward-looking statements are reasonable, undue reliance should not be placed on them as actual results may differ materially from these forward-looking statements. The forward-looking statements contained in this news release are made as of the date hereof, and the Company undertakes no obligation to update publicly or revise any forward-looking statements or information, except as required by law. FOR MORE INFORMATION, PLEASE CONTACT:Investor Relations:ir@portagebiotech.com Media Relations:media@portagebiotech.com

临床研究免疫疗法

2024-04-12

·FierceBiotech

Portage Biotech hints at potential closure as it halts programs, hunts for strategic options

Portage Biotech said in January that it was halting development of its iNKT programs. Portage Biotech is putting the clamps on existing work to save cash as it prioritizes a hunt for strategic alternatives. The company said Friday that after a review of the financing market and the amount of spending necessary to advance its pipeline, the search for strategic alternatives would commence. In the meantime, Portage is halting enrollment in a clinical trial testing both its adenosine 2A inhibitor PORT-6 and its adenosine 2B inhibitor PORT-7. Portage bought both assets from Tarus Therapeutics less than two years ago. Portage is considering anything from securing partners for its assets to a merger, sale or a full wind-down of the company. The biotech has no timetable for finding a path forward. About three months ago, Portage said it was all in on prioritizing development of its adenosine inhibitors, electing to pause further development of an iNKT program. The biotech had been expecting to provide interim data from a phase 1a trial testing PORT-6 in patients with solid tumors at this year’s American Society of Clinical Oncology annual meeting in June, with final data teased for November. But the company had little money to work with, entering 2024 with just $5.3 million in cash on hand, according to a full-year earnings report from February. Still, Portage affirmed at the time that it intended to press ahead with its adenosine work. Those assets were acquired from Tarus back in July 2022, with Portage handing over 2.4 million shares and taking on $3 million in liabilities. In addition to PORT-6 and PORT-7, Portage took hold of a dual adenosine inhibitor, PORT-8, and a preclinical candidate to treat gastrointestinal tumors, dubbed PORT-9. But neither PORT-8 or PORT-9 are still in development, according to Portage’s pipeline.