The activation of histone deacetylases 4 prevented endothelial dysfunction: A crucial mechanism of HuangqiGuizhiWuwu Decoction in improving microcirculation dysfunction in diabetes

Article

作者: Chen, Yongjun ; Zhang, Kaitong ; Chen, Xinyi ; Gu, Jiangyong ; Yan, Yue ; Wang, Chen ; Su, Weiwei ; Zhang, Meng ; Cai, Gaize ; Cheng, Hong ; Xia, Xiaoye ; Chen, Meijiang ; Yao, Lin ; Jiang, Haiqiang

ETHNOPHARMACOLOGICAL RELEVANCE:

The regulation of epigenetic factors is considered a crucial target for solving complex chronic diseases such as cardio-cerebrovascular diseases. HuangqiGuizhiWuwu Decoction (HGWWD), a classic Chinese prescription, is mainly used to treat various vascular diseases. Although our previous studies reported that HGWWD could effectively prevent vascular dysfunction in diabetic rodent models, the precise mechanism is still elusive.

AIM OF THE STUDY:

In this study, we investigated the epigenetic mechanisms of modulating the damage of vascular endothelial cells in diabetes by HGWWD.

METHODS:

We first analyzed common active components of HGWWD by using HPLC-Q-TOF-MS/MS analysis, and predicted the isoforms of histone deacetylase (HDAC) that can potentially combine the above active components by systems pharmacology. Next, we screened the involvement of specific HDAC isoforms in the protective effect of HGWWD on vascular injury by using pharmacological blockade combined with the evaluation of vascular function in vivo and in vitro.

RESULTS:

Firstly, HDAC1, HDAC2, HDAC3, HDAC4, HDAC6, HDAC7, SIRT2, and SIRT3 have been implicated with the possibility of binding to the thirty-one common active components in HGWWD. Furthermore, the protective effect of HGWWD is reversed by both TSA (HDAC inhibitor) and MC1568 (class II HDAC inhibitor) on vascular impairment accompanied by reduced aortic HDAC activity in STZ mice. Finally, inhibition of HDAC4 blocked the protective effect of HGWWD on microvascular and endothelial dysfunction in diabetic mice.

CONCLUSIONS:

These results prove the key role of HDAC4 in diabetes-induced microvascular dysfunction and underlying epigenetic mechanisms for the protective effect of HGWWD in diabetes.

2022-08-28·Journal of oncology

Histone Deacetylase Inhibitor I3 Induces the Differentiation of Acute Myeloid Leukemia Cells with t (8; 21) or MLL Gene Translocation and Leukemic Stem-Like Cells

Article

作者: Duan, Yu ; Zhao, Mengjie ; Wei, Liuya ; Chen, Zhe-Sheng ; Wang, Jiangyun ; Hu, Zhenbo ; Zhao, Yao ; Liu, Yong ; Wang, Haihua ; Zhang, Lei

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by the clonal expansion and differentiation arrest of leukemic cells in peripheral blood and bone marrow. Though the treatment using cytarabine-based protocol for AML patients with t (8; 21) translocation has improved the 5-year overall survival rate, drug resistance continues to be the principal limiting factor for the cure of the disease. In addition, very few AML patients with mixed lineage leukemia gene rearrangements (MLLr) have a desirable outcome. This study evaluated the cell differentiation effect of a potent HDAC (histone deacetylase) inhibitor, I3, and its possible mechanism on the AML cells with t (8; 21) translocation or MLLr and leukemic stem-like cells (Kasumi-1, KG-1, MOLM-13, and THP-1). I3 exhibited efficient anti-proliferative activity on these cells via promoting cell differentiation, accompanied by the cell cycle exit at G0/G1. Importantly, I3 showed the properties of HDAC inhibition, as assessed by the acetylation of histones H3 and H4, which resulted in blocking the activation of the VEGF (vascular endothelial growth factor)-MAPK (mitogen-activated protein kinase) signaling pathway in the Kasumi-1 cell line. These data demonstrate that I3 could be a potent chromatin-remodeling agent to surmount the differentiation block in AML patients, including those with t (8; 21) translocation or MLLr, and could be a potent and selective agent for AML treatment.

2021-08-27·Mutagenesis3区 · 医学

Trichostatin A mitigates radiation-induced teratogenesis in C57Bl/6 mice

3区 · 医学

Article

作者: Haritwal, Teena ; Goyal, Nikita ; Agrawala, Paban K ; Gupta, Noopur ; Parvez, Suhel

Abstract:

Radiation exposure in utero is known to lead to serious concerns to both the mother and children, including developmental anomalies in the children. In the recent past, trichostatin A, an HDAC (histone deacetylase) inhibitor and epigenetic modifier, has been shown to mitigate radiation-induced anomalies in the male reproductive system of C57BL/6 mice. Therefore, the current study was undertaken to evaluate the mitigating effects of trichostatin A (TSA) against radiation-induced developmental anomalies in mice. Foetuses of in utero whole-body gamma-irradiated mice during the active organogenesis period were examined for developmental anomalies at 8.5 and 18.5 days of gestation. In utero radiation exposure caused developmental anomalies like microcephaly, microphthalmia, gastroschisis and kinky tail besides prenatal mortality. TSA administration post-irradiation was observed to reduce 50% of prenatal mortality at E18.5 by reducing congenital and developmental anomalies. Observation of such results could be corroborated with the HDAC inhibitory potential of TSA knowing that developmental anomalies may have epigenetic origin. TSA, therefore, can be considered as a potential radiomitigator.

项与 NBM-B-OS-05 相关的新闻（医药）

2022-11-15

·PRNewswire

Shuttle Pharmaceuticals Provides Third Quarter 2022 Corporate Update

ROCKVILLE, Md., Nov. 15, 2022 /PRNewswire/ -- Shuttle Pharmaceuticals Holdings, Inc. (Nasdaq: SHPH), a discovery and development stage specialty pharmaceutical company focused on improving the outcomes of cancer patients treated with radiation therapy (RT), today provided a corporate update in connection with the filing of its Quarterly Report on Form 10-Q for the quarter ended September 30, 2022. Recent Highlights Completed an initial public offering ("IPO") raising gross proceeds of $10.0 million with listing of its common shares on the Nasdaq Capital Market. Closed on the overallotment option resulting in additional gross proceeds of $1.5 million. Entered into an agreement with TCG GreenChem, Inc. to manufacture Ropidoxuridine, the Company's lead clinical sensitizer drug candidate, for use in formulating the drug product for testing in clinical trials of Ropidoxuridine and RT of cancers. Engaged Theradex Oncology, a leading clinical research organization, to help prepare for its upcoming clinical study of Ropidoxuridine. Awarded patents in the U.S. and Hong Kong for its radiation sensitizing HDAC inhibitor technology platform. Appointed Dr. Bette Jacobs to its Board of Directors as an independent director. "The past few months have been exciting for Shuttle as we completed our IPO and made progress on a number of important activities in the advancement of our lead clinical sensitizer drug candidate, Ropidoxuridine, aimed at improving the outcomes of cancer treatment through radiation therapy while reducing its side effects," commented Shuttle Pharma's Chairman and CEO, Anatoly Dritschilo, M.D. "With a Phase I clinical trial of Ropidoxuridine and radiation therapy completed in patients with advanced colorectal cancers to establish the maximum tolerated dose and levels of drug availability in the blood after oral administration, our next steps are to perform a Phase II clinical trial in brain cancer patients undergoing radiation therapy for glioblastoma. We are preparing the Investigational New Drug application for the study with an expectation of final submission to the FDA in the second quarter of 2023. I look forward to continued progress in the quarters ahead as we look to execute on our mission to deliver innovative new treatments to thousands of patients who currently lack effective therapies." The Ropidoxuridine Opportunity Radiation therapy is a proven modality for cancer treatment. By developing radiation sensitizers, Shuttle Pharma aims to increase cure rates, prolong patient survival and improve quality of life when radiation is used as a primary treatment, or in combination with surgery, chemotherapy and immunotherapy. Modern oncology incorporates multi-modality strategies that use combinations of surgery, chemo or immunotherapy, and radiation to treat cancers. Radiation therapy requires delivery and shaping of high doses of radiation energy to tumors to kill or slow the growth of cancer cells by damaging their cellular DNA. State-of-the-art technologies to deliver the radiation doses include image guided treatments with linear accelerators and particle radiation with protons. However, radiation therapy of adjacent healthy tissues can lead to injuries of normal organs. The addition of radiation sensitizers allows preferential increased killing of cancer cells. Currently, there is only one drug on the market approved by the FDA as a radiation sensitizer. However, that drug has a host of side effects that limit its utility. Other drugs are used "off label" by radiation oncologists, but these often have additional side effects. There is an urgent need for an effective radiation sensitizer with low toxicity for use in combination with radiation therapy. The Company's lead candidate, Ropidoxuridine, is an orally available prodrug, that once ingested, metabolizes into iododeoxyuridine, a pyrimidine analog, that has been recognized as a radiosensitizing agent since the 1960's. Various sources have estimated that more than 800,000 patients are treated annually in the U.S. with radiation therapy for their cancers. About 50% are treated for curative purposes and the balance for palliative care. The market opportunity for radiation sensitizers lies with the 400,000 patients treated with curative intent. Based on a rough estimate of a course of radiation sensitizing brand drug therapy, which are used off label at this time, the potential market size is estimated to be in excess of $4.0 billion annually. Manufacturing Agreement In September 2022, the Company announced it entered into an agreement with TCG GreenChem, Inc. to manufacture Ropidoxuridine, the Company's lead clinical sensitizer drug candidate, for use in formulating the drug product for testing in clinical trials of Ropidoxuridine and RT of cancers. The agreement with TCG GreenChem allows the Company to advance its clinical research, including its proposed Phase II clinical trials, to establish the data necessary for the FDA to determine efficacy in treating brain tumors, sarcomas and pancreatic cancers, diseases that offer potential for orphan designations. In conjunction with manufacturing Ropidoxuridine, TCG GreenChem will perform process research, development and optimization work for Shuttle Pharma related to Ropidoxuridine and create working standards of starting materials and intermediates to support the qualitative/quantitative analysis of the drug reaction progress, determination of impurities, total mass balance and assay yields of the reactions. Shuttle Pharma will own all intellectual property and improvements developed through the Manufacturing Agreement. TCG GreenChem, Inc. was founded by former large pharma pharmaceutical executives with a track record in the development of hundreds of New Chemical Entities into the clinic and commercialization of several well-known pharmaceutical products for Boehringer Ingelheim Pharmaceuticals, Inc., Sepracor, Inc., and Merck & Co, Inc. Engagement of Theradex Oncology In November 2022, Shuttle announced it had engaged Theradex Oncology, a leading clinical research organization ("CRO"), to help prepare for its upcoming clinical study of Ropidoxuridine. Specifically, Theradex Oncology will assist the Company in meetings with the FDA and preparation of the IND (Investigational New Drug) application for the planned Phase II clinical study of Ropidoxuridine and radiation therapy. Theradex's expertise in regulatory and statistical design is particularly helpful in meeting FDA requirements and providing guidance in study design and statistical support for the clinical trial. Theradex Oncology has provided full oncology clinical trial services in the U.S. and Europe for over three decades. Meg Valnoski, president of Theradex, will be directly involved in the regulatory support provided to Shuttle Pharmaceuticals, working closely with a diverse team of experts to ensure the successful execution of clinical trials. Patent Awards In September 2022, Shuttle Pharma announced it had been awarded patents in the U.S. and Hong Kong for its radiation sensitizing HDAC inhibitor technology platform, which is focused on reducing side effects and improving outcomes for cancer patients treated with radiation therapy (RT). Histone deacetylase (HDAC) inhibitors have been described as "a novel class of drugs that target enzymes involved in regulation of critical cellular functions that can inhibit cancer growth and activate cellular immunity," according to Scott Grindrod, PhD, lead inventor and Laboratory Director at Shuttle Pharmaceuticals. Treatment with HDAC inhibitors allows regulation of gene expression by blocking HDAC enzyme activity and allowing genes to be "turned on" to express proteins involved in regulation of the cell cycle, DNA damage response and immune activation. Inhibiting HDAC enzymes can turn on tumor suppressor genes to help control cell division and slow down cancer progression. Non-cytotoxic, highly selective inhibitors target the histone deacetylase 6 (HDAC6) enzyme to stimulate the immune system for applications in the treatment of cancers, neurological diseases and immunological disorders. About Shuttle Pharmaceuticals Founded in 2012 by faculty members of the Georgetown University Medical Center, Shuttle Pharmaceuticals is a discovery and development stage specialty pharmaceutical company focused on improving the outcomes for cancer patients treated with radiation therapy (RT). Our mission is to improve the lives of cancer patients by developing therapies that are designed to maximize the effectiveness of RT while limiting the side effects of radiation in cancer treatment. Although RT is a proven modality for treating cancers, by developing radiation sensitizers, we aim to increase cancer cure rates, prolong patient survival and improve quality of life when used as a primary treatment or in combination with surgery, chemotherapy and immunotherapy. For more information, please visit our website at . Safe Harbor Statement Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute "forward-looking statements." These statements include, but are not limited to, statements concerning the development of our company. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," "target," "will," "would" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including factors discussed in the "Risk Factors" section of Shuttle Pharma's IPO prospectus filed with the SEC on August 31, 2022, and any risk factors set forth in the Company's Quarterly Report on Form 10-Q filed with the SEC on November 14, 2022, or any other SEC filings. Any forward-looking statements contained in this press release speak only as of the date hereof and, except as required by federal securities laws, Shuttle Pharmaceuticals specifically disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise. Shuttle Pharmaceuticals Anatoly Dritschilo, M.D., CEO 240-403-4212 [email protected] Investor Contacts Lytham Partners, LLC Robert Blum 602-889-9700 [email protected] SOURCE Shuttle Pharmaceuticals Holdings, Inc.

临床2期放射疗法

2022-11-14

·BioSpace

Rakovina Therapeutics Announces Publication Highlighting Activity of Novel Bi-functional PARP-HDAC Inhibitor in Preclinical Models of Ewing Sarcoma

Publication to be available on pre-print server, bioRxiv, and will be submitted for scientific journal peer-review VANCOUVER, British Columbia, Nov. 14, 2022 (GLOBE NEWSWIRE) -- Rakovina Therapeutics Inc. (TSX-V: RKV) (“the Company”), today announced publication of a scientific article on the anti-cancer activity of the Company’s novel dual PARP-HDAC inhibitor in models of Ewing sarcoma. The manuscript entitled “A bi-functional PARP-HDAC inhibitor with activity in Ewing sarcoma”, indicate a benefit of dual PARP and HDAC inhibition and provide proof-of-concept for a bi-functional single-molecule therapeutic strategy in the treatment of Ewing sarcoma. Ewing sarcoma is a highly aggressive bone and soft tissue tumor affecting mainly children and young adults, with a dismal 5-year survival rate of 15-30% for metastatic disease. Previous studies have demonstrated that Ewing sarcoma cells are sensitive to FDA-approved PARP inhibitors, but clinical trials have failed to produce a durable treatment response. PARP inhibitors have been demonstrated to impact tumors that harbor BRCA mutations or other defects in homologous repair (HR). This concept is commonly referred to as “BRCAness”. Ewing sarcoma is characterized by the presence of a genetic fusion involving the EWSR1 gene. This fusion has been shown to impair HR activity indicating a level of “BRCAness” in Ewing sarcoma. The lack of clinical response in Ewing sarcoma to treatment with single-agent PARP inhibitors supports employing combination therapy strategies that further inhibit HR and increase BRCAness in Ewing sarcoma. Recent studies in leukemia, breast cancer, liver cancer, glioblastoma, prostate cancer and anaplastic thyroid models demonstrated suppression of HR following treatment with HDAC inhibitors, supporting the synergistic potential of dual HDAC and PARP inhibition. Rakovina Therapeutics researchers characterized and tested kt-3283, a novel dual-function single molecule of PARP and HDAC in Ewing sarcoma model systems. In these studies, kt-3283 demonstrated higher efficacy than treatment with single-agent PARP or HDAC inhibitors. These data indicate the dual activity of kt-3283 is 30- to 80-times more potent in Ewing sarcoma models than an FDA-approved PARP inhibitor, and 30- to 60-times more potent than an FDA-approved HDAC inhibitor. In an Ewing sarcoma metastasis model, kt-3283 prevented metastatic cancer growth in the lungs of mice inoculated with an aggressive Ewing sarcoma cell line. “These results provide proof-of-concept for a novel single-molecule PARP-HDAC inhibitor in the treatment of Ewing sarcoma,” stated Prof. Mads Daugaard Rakovina Therapeutics’ president and chief scientific officer. “This concept will likely be relevant in other cancer indications beyond Ewing sarcoma and potentially offer an opportunity to suppress therapeutic resistance to PARP-inhibitor treatment.” Development of Rakovina Therapeutics’ novel kt-3000 DNA-damage response inhibitors is supported, in part, by the St. Baldrick’s Foundation Martha’s BEST Grant for All, which is aimed at developing new treatments for Ewing sarcoma, an aggressive bone and soft tissue cancer in children and young adults. About Rakovina Therapeutics Inc. Rakovina Therapeutics Inc. is focused on the development of new cancer treatments based on novel DNA-damage response (DDR) technologies. The Company has established a pipeline of novel DNA-damage response inhibitors with the goal of advancing one or more drug candidates into human clinical trials and obtaining marketing approval for new cancer therapeutics from Health Canada, the United States Food and Drug Administration and similar international regulatory agencies. Further information may be found at . Additional Information The TSXV has neither approved nor disapproved the content of this press release. Neither the TSXV nor its Regulation Services Provider (as that term is defined in policies of the TSXV) accepts responsibility for the adequacy or accuracy of this release. Notice regarding forward-looking statements: This release includes forward-looking statements regarding the Company and its respective business, which may include, but is not limited to, statements with respect to the proposed business plan of the Company and other statements. Often, but not always, forward-looking statements can be identified by the use of words such as “plans”, “is expected”, “expects”, “scheduled”, “intends”, “contemplates”, “anticipates”, “believes”, “proposes” or variations (including negative variations) of such words and phrases, or state that certain actions, events, or results “may”, “could”, “would”, “might” or “will” be taken, occur or be achieved. Such statements are based on the current expectations of the management of the Company. The forward-looking events and circumstances discussed in this release may not occur by certain specified dates or at all and could differ materially as a result of known and unknown risk factors and uncertainties affecting the Company, including risks regarding the medical device industry, economic factors, regulatory factors, the equity markets generally and risks associated with growth and competition. Although the Company has attempted to identify important factors that could cause actual actions, events, or results to differ materially from those described in forward-looking statements, there may be other factors that cause actions, events, or results to differ from those anticipated, estimated or intended. No forward-looking statement can be guaranteed. Except as required by applicable securities laws, forward-looking statements speak only as of the date on which they are made and the Company undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, or otherwise. The reader is referred to the Company’s most recent filings on SEDAR for a more complete discussion of all applicable risk factors and their potential effects, copies of which may be accessed through the Company’s pro at . Contact: Rakovina Therapeutics Inc. David Hyman Chief Financial Officer Email: info@rakovinatherapeutics.com Investor Relations Contact IR@rakovinatherapeutics.com Media Contact MEDIA@rakovinatherapeutics.com

临床结果

2022-10-31

·BioSpace

Rakovina Therapeutics Announces Preclinical Data Presentation at the 34th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium

VANCOUVER, British Columbia, Oct. 31, 2022 (GLOBE NEWSWIRE) -- Rakovina Therapeutics Inc. (TSX-V: RKV) (“the Company”), a biopharmaceutical company committed to advancing new cancer therapies based on novel DNA-damage response (DDR) technologies, is pleased to announce the presentation of new data during the 34th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium, which was held in Barcelona Spain October 26-28, 2022. “Data presented at the conference demonstrate our continued progress toward confirmation of a lead compound from our kt-3000 series for advancement to human clinical trials,” stated Prof. Mads Daugaard, Rakovina Therapeutics president and chief scientific officer. Rakovina Therapeutics’ kt-3000 series represents a novel class of bi-functional small-molecule drug candidates that has been designed to combine inhibition of both poly(ADP)-ribose polymerase (PARP) and histone deacetylase (HDAC) in a single molecule as a novel approach to providing meaningful clinical benefit to cancer patients. “The 3D spheroid models discussed at the symposium closely mimic solid tumors and constitute an attractive high-throughput pre-clinical test system for validating the potential experimental drug candidates. Our kt-3000 prototype lead compound performs 30-40 times better than the FDA-approved PARP inhibitor olaparib (Lynparza®) and 5-10 times better than the FDA-approved HDAC-inhibitor vorinostat (Zolina®) in Ewing sarcoma 3D spheroid models. This provides strong proof-of-concept validation of our kt-3000 potential to address significant unmet needs in the treatment of solid tumors,” added Prof. Daugaard. Pre-clinical studies have revealed the potential for synergy in the treatment of solid tumors by combining a PARP inhibitor with inhibition of histone deacetylase (HDAC) enzymes. In clinical practice, however, the benefits of combination treatments are often limited due to differing pharmacokinetics and overlapping toxicities requiring sequential administration. The EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium is a joint annual meeting of the European Oncology Research and Therapeutics Consortium, the US National Cancer Institute and the American Association for Cancer Research. The meeting focuses on preclinical and phase I human clinical trials, enabling and facilitating in-depth scientific discussions on the latest developments in therapeutic targets and experimental drugs and attracts academics, scientists and pharmaceutical industry representatives from around the globe. Rakovina Therapeutics has previously presented preclinical data at peer reviewed scientific meetings demonstrating the potential of kt-3000 series drug candidates against treatment-resistant cancer cell lines. Development of the kt-3000 series is supported, in part, by the St. Baldrick’s Foundation Martha’s BEST Grant for All, which is aimed at developing new treatments for Ewing sarcoma, an aggressive bone and soft tissue cancer in children and young adults. Rakovina Therapeutics scientific presentations, including yesterday’s poster from the AACR Special Conference on Sarcomas can be found on the Company’s website. About Rakovina Therapeutics Inc. Rakovina Therapeutics Inc. is focused on the development of new cancer treatments based on novel DNA-damage response (DDR) technologies. The Company has established a pipeline of novel DNA-damage response inhibitors with the goal of advancing one or more drug candidates into human clinical trials and obtaining marketing approval for new cancer therapeutics from Health Canada, the United States Food and Drug Administration and similar international regulatory agencies. Further information may be found at . Additional Information The TSXV has neither approved nor disapproved the content of this press release. Neither the TSXV nor its Regulation Services Provider (as that term is defined in policies of the TSXV) accepts responsibility for the adequacy or accuracy of this release. Notice regarding forward-looking statements: This release includes forward-looking statements regarding the Company and its respective business, which may include, but is not limited to, statements with respect to the proposed business plan of the Company and other statements. Often, but not always, forward-looking statements can be identified by the use of words such as “plans”, “is expected”, “expects”, “scheduled”, “intends”, “contemplates”, “anticipates”, “believes”, “proposes” or variations (including negative variations) of such words and phrases, or state that certain actions, events, or results “may”, “could”, “would”, “might” or “will” be taken, occur or be achieved. Such statements are based on the current expectations of the management of the Company. The forward-looking events and circumstances discussed in this release may not occur by certain specified dates or at all and could differ materially as a result of known and unknown risk factors and uncertainties affecting the Company, including risks regarding the medical device industry, economic factors, regulatory factors, the equity markets generally and risks associated with growth and competition. Although the Company has attempted to identify important factors that could cause actual actions, events, or results to differ materially from those described in forward-looking statements, there may be other factors that cause actions, events, or results to differ from those anticipated, estimated or intended. No forward-looking statement can be guaranteed. Except as required by applicable securities laws, forward-looking statements speak only as of the date on which they are made and the Company undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, or otherwise. The reader is referred to the Company’s most recent filings on SEDAR for a more complete discussion of all applicable risk factors and their potential effects, copies of which may be accessed through the Company’s pro at . Contact: Rakovina Therapeutics Inc. David Hyman Chief Financial Officer Email: info@rakovinatherapeutics.com Investor Relations Contact IR@rakovinatherapeutics.com Media Contact MEDIA@rakovinatherapeutics.com

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