ABSTRACT 2′-Fluoro-5-methyl-β- l -arabinofuranosyluracil ( l -FMAU) is the first l -nucleoside analog with low cytotoxicity discovered to have potent antiviral activities against both hepatitis B virus and Epstein-Barr virus but not human immunodeficiency virus. This spectrum of activity is different from those of the other l -nucleoside analogs examined. l -FMAU enters cells through equilibrative-sensitive and -insensitive nucleoside transport as well as through nonfacilitated passive diffusion. l -FMAU is phosphorylated stepwise in cells to its mono-, di-, and triphosphate forms. In the present study the enzymes responsible for the first step of l -FMAU phosphorylation were identified. This is the first thymidine analog shown to be a substrate not only for cytosolic thymidine kinase and mitochondrial deoxypyrimidine kinase but also for deoxycytidine kinase. This finding suggests that the antiviral activity of l -FMAU will not be limited by the loss or alteration of any of these deoxynucleoside kinases.
Abstract Immune checkpoint blockade therapy has recently been recognized as a breakthrough in cancer treatment. Currently the FDA has approved Ipilimumab (anti-CTLA4), Pembrolizumab (anti-PD1) and Nivolumab (anti-PD1), and Atezolizumab (anti-PDL1) for the treatment of several types of cancers, including melanoma. However, colitis and diarrhea are commonly found in these immunotherapies, particularly in anti-PD1/CTLA4 therapy. PHY906(YIV-906) is inspired by the Huang Qin Tang, which was first described in Chinese texts 1800 years ago for the treatment of numerous gastrointestinal symptoms. Consistent preparations of PHY906 could be manufactured apart 10 years. In animal studies, PHY906 can increase the anti-tumor activity of a broad spectrum of chemotherapies while promoting damaged intestinal tissue recovery via mutliple targets. Several clinical results suggest that PHY906 had potential to increase the therapeutic index of cancer treatments (chemotherapy, radiation) by prolonging life and improving patient quality of life. We hypothesize that PHY906 can reduce diarrhea caused by anti-PD-L1, anti-PD1, and/or in combination with CTL4 without compromising their anti-tumor activity. We studied the effect of PHY906 in combination with anti-PDL1, anti-PD1, anti-CTLA4 and anti-PD1/CTLA4, using subcutaneously implanted B16F10 melanoma in Black B16 mice. Results indicated that PHY906 enhanced the anti-tumor activity of anti-PD1, anti-PDL1, or anti-PD1/CTLA4; but not anti-CTLA4 alone, in vivo. In addition, PHY906 did not compromise the action of anti-PD-L1 in brain implanted B16 tumor. PHY906 in combination with all of the antibodies had no impact of body weight change or different type of blood cells counts. PHY906 reduced mRNA expression of several inflammation markers, including TNFa, MCP1, ICAM, IL2, in ileum or colon tissues following anti-PD1 or anti-CTLA4 treatment. In cell culture, PHY906 was found to have modulation effect on Indoleamine 2,3-dioxygenase (IDO) which is a key resistance factor to immune checkpoint blockade therapies. Overall, PHY906 can increase the therapeutic index for anti-PDL1, antiPD1, or anti-PD1/CTLA4 in against melanoma. We are planning to initiate a clincal trial to determine if PHY906 could enhance the therapeutic index of anti-PD1/CTLA4 for the treatment fo melanoma in patient. This work was supported by grant (1PO1CA154295-01A1) from National Cancer Institute (NCI), NIH, USA. Dr. Yung-Chi Cheng is a fellow of National Foundation for Cancer Research (NFCR), USA. Citation Format: Wing Lam, Zaoli jiang, Xue han, Shwu-Huey Liu, Lieping Chen, YungChi Cheng. PHY906(YIV-906), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Immune checkpoint blockade therapy: anti-PDL1, anti-PD1, anti-PD1/CTLA4 against melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5584. doi:10.1158/1538-7445.AM2017-5584
Abstract Prostate cancer is the second leading cause of cancer death among men in the United States. Androgen or Androgen receptor (AR) targeted therapy is a strategy for the treatment of prostate cancer, however, long-term treatment with androgen deprivation therapy inevitably leads to the development of Castration-Resistant Prostate Cancer (CRPC). AR variants and glucocorticoid receptor (GR) (replacing AR function) are two key factors to promote resistance to AR-targeting therapies in CRPC patients. Developing a multi-targeted drug that can inhibit both the AR variant and GR action could help overcome drug resistance, increase durability, and improve the therapeutic outcome for prostate cancer patients. Through our STAR (Signal, Transduction, Activity, and Response) Drug Discovery Platform, we studied the effects of three hundred medicinal plant extracts across 25 signaling pathways to identify a drug candidate. YIV-818-A was developed as a novel drug candidate based on optimized water extracts of Rubia cordifolia (R.C). R.C collected from different sources had different quantities of compound X. The amount of compound X of R.C could be correlated to the potency of AR inhibition. YIV-818-A was able to inhibit DHT or Dexamethasone (DEX) induced luciferase activity of 22RV1 cells which were harboring ARE luciferase reporter. Using activity guided purification of YIV-818-A, compound X was identified as the key active compound for inhibiting AR and GR activities. YIV-818-A and compound X could down regulate both AR (full length) and AR-V (splice variants) protein but not GR protein of 22RV1 cells. YIV-818-A and compound X could also inhibit KLK2, and PSA (AR target genes) mRNA expression induced by DHT or SGK (GR target gene) mRNA expression induced by DEX. YIV-818-A and compound X had the potential to affect epigenetics of 22RV1 cells by down-regulating Brd2 and Brd4 (BET: bromodomain and extra-terminal proteins which could serve as epigenetic readers to promote AR or GR-dependent gene transcription) and reduce histone 3 lysine 27 acetylation (H3K27Ac), which is required for BRDs binding, but not H3K9Ac or K14Ac. Most importantly, YIV-818-A and compound X showed synergies with apalutamide, darolutamide and enzalutamide to inhibit AR activity and growth of 22RV1 cells. In conclusion, YIV-818-A and compound X could overcome drug resistance caused by AR variants and GR by down-regulating AR protein, inhibiting GR function and epigenetic regulation. YIV-818-A and compound X could enhance anti-prostate cancer drug action against CRPC. R.C has a long history of safe, human usage in Asia as a dietary supplement for improving health. Given R.C.’s safety profile, YIV-818-A also could be developed as a chemoprevention agent and/or anti-cancer prostate cancer drug. Citation Format: Wing Lam, Mohammad Arammash, Wei Cai, Rong Hu, Shwu-Huey Liu, Peikwen Cheng, Yung-chi Cheng. YIV-818-A enhanced apalutamide, darolutamide and enzalutamide action for prostate cancer treatment by down-regulating androgen receptor protein, inhibiting glucocorticoid receptor function and epigenetic regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3078.
557 PHY906 is a traditional Chinese botanical formulation consisting of 4 different herbs, and it has been used for some 1800 years to treat gastrointestinal ailments, some of which are commonly observed side effects in cancer patients undergoing chemotherapy. We have previously reported that PHY906 reduced chemotherapy-induced toxicities including body weight loss and mortality, and that it also enhanced the antitumor efficacy of a broad-spectrum of anticancer agents, such as CPT-11, 5-FU, CPT-11/5-FU/LV, VP-16, and L-OddC in in vivo animal models. PHY906 has been co-administrated with either the oral 5-FU prodrug capecitabine or CPT-11 in human hepatocellular xenografts mouse model, and with gemcitabine in mouse pancreatic cancer model. We have shown that PHY906 significantly enhanced the therapeutic index of chemotherapeutic agents studied in both hepatocellular and pancreatic cancer models. Co-administration of PHY906 with either capecitabine or gemcitabine in animal models did not alter the pharmacokinetic profile of capecitabine, gemcitabine, or their respective metabolites. Our biochemical studies revealed that the PHY906 formulation possesses a wide range of pharmacological activities. The potential mechanism(s) of action of PHY906 include (1) enhancement of oral uptake of pharmacologically active agents with inhibition in intestinal CYP3A4; (2) inhibition of NF-κB activity; (3) inhibition of MMP activity; and (4) destruction of the integrity of sinusoids in hepatoma. These pre-clinical in vivo studies have provided rationale for developing PHY906 in the clinical setting. A phase I/IIA double-blind placebo-controlled, dose escalation study of PHY906 was initiated to evaluate the potential effect of PHY906 in modulating CPT-11-induced diarrhea associated with the bolus, weekly schedule of CPT-11/5-FU/LV in advanced colorectal cancer patients. A second phase I/II open-label dose escalation clinical trial has just been opened to patient accrual to evaluate the role of PHY906 in combination with capecitabine in the treatment of hepatocellular carcinoma.
TPS601 Background: First-line systemic treatment options for advanced HCC pts are limited to the multi-targeted tyrosine kinase inhibitors, SORA and lenvatinib. Both agents improve outcomes for pts with advanced disease, but are associated with increased rate of grade ≥ 3 treatment-related adverse events. YIV-906 (PHY906, KD018) is derived from Huang-Qin-Tang, a traditional Chinese medicine documented 1800 years ago to treat gastrointestinal ailments. Preclinical data indicate YIV-906 increases inflammation in the tumor microenvironment by M1 macrophages activation/proliferation resulting in HCC tumor rejection in vivo and reduces SORA associated toxicity. Clinical experience with YIV-906 plus SORA suggests safety and potential clinical benefit to HCC pts with chronic HBV infection. Methods: This is a proof-of-concept, international, multicenter, double-blind, placebo-controlled, randomized phase 2 study designed to compare the efficacy of YIV-906 and SORA to SORA alone in advanced HCC pts (NCT04000737). Key eligibility criteria include age ≥ 18 years, HBV-associated HCC, ≥ 1 measurable untreated lesion, Child-Pugh A liver function, and no prior systemic therapy. An estimated 125 pts will be randomized 2:1 to receive the investigational (YIV-906 plus SORA) or control (placebo plus SORA) arm until disease progression or unacceptable toxicity. Pts will be stratified by metastatic status (extrahepatic/vascular invasion vs none) and ECOG performance status (0 vs. 1). The primary endpoint is progression-free survival (PFS). Secondary endpoints include objective response rate and disease control rate by mRECIST, time to progression, overall survival, quality of life, and safety by CTCAE version 4.0. Translational correlatives include pharmacokinetics, effects on oral/gut microbiota, and exploratory soluble biomarkers analysis. For the primary endpoint, sample size of 41 pts in control arm and 84 pts in the investigational arm achieves 90% power at a 0.05% significance level to detect a hazard ratio of 0.5 assuming the median PFS of the control SORA arm is 3.6 months and that of the combination arm is 7.3 months. Clinical trial information: NCT04000737.
ABSTRACT 2′,3′-Dideoxy-2′,3′-didehydro-β- l (−)-5-fluorocytidine [ l (−)Fd4C] has been reported to be a potent inhibitor of the human immunodeficiency virus (HIV) in cell culture. In the present study the antiviral activity of this compound in two-drug combinations and its intracellular metabolism are addressed. The two-drug combination of l (−)Fd4C plus 2′,3′-didehydro-2′,3′-dideoxythymidine (D4T, or stavudine) or 3′-azido-3′-deoxythymidine (AZT, or zidovudine) synergistically inhibited replication of HIV in vitro. Additive antiviral activity was observed with l (−)Fd4C in combination with 2′,3′-dideoxycytidine (ddC, or zalcitabine) or 2′,3′-dideoxyinosine (ddI, or didanosine). This β- l (−) nucleoside analog has no activity against mitochondrial DNA synthesis at concentrations up to 10 μM. As we previously reported for other β- l (−) nucleoside analogs, l (−)Fd4C could protect against mitochondrial toxicity associated with D4T, ddC, and ddI. Metabolism studies showed that this drug is converted intracellularly to its mono-, di-, and triphosphate metabolites. The enzyme responsible for monophosphate formation was identified as cytoplasmic deoxycytidine kinase, and the K m is 100 μM. l (−)Fd4C was not recognized in vitro by human mitochondrial deoxypyrimidine nucleoside kinase. Also, l (−)Fd4C was not a substrate for deoxycytidine deaminase. l (−)Fd4C 5′-triphosphate served as an alternative substrate to dCTP for incorporation into DNA by HIV reverse transcriptase. The favorable anti-HIV activity and protection from mitochondrial toxicity by l (−)Fd4C in two-drug combinations favors the further development of l (−)Fd4C as an anti-HIV agent.
Abstract Immune checkpoint blockade therapy has recently been recognized as a breakthrough in cancer treatment. Recently, FDA has approved Nivolumab (anti-PD1) for the treatment of hepatocellular carcinoma (HCC) patients previously treated with sorafenib. However, the percentage of patients with a complete response was only 1.9% that is much lower than Nivolumab used for treating melanoma. Diarrhea, nausea and fatigue are common side effects for HCC patients who received Nivolumab. YIV906(PHY906) is inspired by the Huang Qin Tang, which was first described in Chinese texts 1800 years ago for the treatment of numerous gastrointestinal symptoms. Consistent preparations of PHY906 can be manufactured apart 10 years. Our clinical results suggest that YIV906 has potential to increase the therapeutic index of capecitabine or sorafenib for HCC patient by improving quality of life and prolonging life. In animal studies, YIV906 can increase the anti-tumor activity of a broad spectrum of chemotherapies through multiple mechanism of actions. We believe that YIV906 could have potential to improve the efficacy of Nivolumab, either by increasing its anti-tumor activity or decreasing its side effects. Here, we studied the effect of YIV906 on the anti-tumor activity of anti-PD1 using BDF1 mice bearing with Hepa 1-6 tumors. Results indicated that YIV906 alone had only moderate effects on the Hepa 1-6 tumor growth. Anti-PD1 alone could stabilize 80% tumor growth and caused 20% tumor shrinkage following 8-day injection. YIV906 plus anti-PD1 made all tumors disappear following 7-day treatment and no tumor rebound was found for one month. When YIV906 and different dosages of anti-PD1 ( 70ug or 200ug per animal) were used, YIV906 plus anti-PD1 (70ug) had an stronger anti-tumor effect than anti-PD1 (200ug) alone. The above results suggested that YIV906 could reduce the usage of anti-PD1 by 3-fold while having better antitumor effects than anti-PD1 alone. qRT-PCR results recovered that many genes related to M1-like macrophages and T cell activation were strongly up-regulated in the tumor tissues following YIV906 plus anti-PD1 treatment. More macrophages were found in tumor tissues associated with an upregulation of MCP1 protein following YIV906 plus anti-PD1 treatment. Biostatical analysis, based on the mRNA expression of M1 and M2-like macrophage signature genes, suggested the tumor microenvironment was favorable for M1 status following YIV906 plus anti-PD1 treatment. In addition, YIV906 could decrease LPS-induced PD1 protein of macrophages in culture. In conclusion, YIV906 might enhance the anti-tumor activity of anti-PD1 by changing the tumor microenvironment favorable to M1-like macrophages. Our results provide supportive information to initialize HCC clinical trial with YIV906 plus Nivolumab. This work was supported by grant (PO1CA154295-01A1) from NCI, USA. Dr. Y.-C. C is a fellow of NFCR, USA. Citation Format: Wing Lam, XiaoChen Yang, Zaoli Jiang, Xue Han, Fulan Guan, William Cheng, Shwu-Huey Liu, Lieping Chen, Yung-Chi Cheng. YIV906 (PHY906) enhanced the antitumor activity of immune checkpoint blockade therapy: Anti-PD1 against liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2724.
Abstract PHY906(YIV-906), a four-herb Chinese medicine formulation, is inspired by an 1800 year-old Chinese formulation called Huang Qin Tang historically used to treat gastrointestinal symptoms. PHY906 can increase the anti-tumor activity of immunotherapy antibodies or chemotherapies while promoting damaged intestinal tissue recovery. Several clinical studies showed that PHY906 had potential to increase the therapeutic index of cancer treatments (chemotherapy, radiation) by prolonging life and improving patient quality of life. When in vivo activities of three different clinical batches (number 6, 10, 11) of PHY906 and F (which is commercial batch of Huang Qin Tang, HQT) was compared to their similarity of chemical profiles, the two set results could not be completely matched. For example, F had very different in vivo activities from PHY906-10 but F clustered closely to PHY906-10 based on their chemical profiles. This information concludes that chemical profile analysis without excluding irrelevant chemicals is not sufficient to evaluate the in vivo activities of a polychemcial mixture. Therefore, we included another two biological platforms based on the in vivo mechanism of action of PHY906 for the quality control. First, we tested the activity of different batches of PHY906 and F on our signaling transduction activity response (STAR) platform which including 18 luciferase reporter cell lines and 2 enzymatic assays. The results of correlation analysis and clustering analysis based on the results from STAR could be matched to in vivo activities of different batches of PHY906 and F. Second, we tested the effect of different batches of PHY906 and F on a set of genes which based on our previous DNA array data in cell culture and the mechanism action of PHY906. Again, the results of correlation analysis and clustering analysis based on qRT-PCR could be matched to to in vivo activities of PHY906 and F. In conclusion, the quality control of a herbal product should be dependent on its usage. Appropriate biological assays based on its mechanism action should be developed for QC for particular usage. Chemical fingerprint has limitation unless irrelevant chemicals had been filter out. Similarity index is only useful when relevant information is used. Mechanism based quality control could be used for other herbal products. This work was supported by grant (1PO1CA154295-01A1) from National Cancer Institute (NCI), NIH, USA. Dr. Yung-Chi Cheng is a fellow of National Foundation for Cancer Research (NFCR), USA. Citation Format: Wing Lam, Yongshen Ren, Fulan Guan, Zaoli jiang, William Cheng, Shwu-Huey Liu, YungChi Cheng. Mechanism based quality control (MBQC) for the four-herb Chinese medicine formulation, PHY906(YIV-906) and other herbal products [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3138. doi:10.1158/1538-7445.AM2017-3138
Abstract YIV-906 (PHY906) is inspired by a traditional 1800-year Chinese herbal formulation, “Huang Qin Tang”, which is commonly used for treating diarrhea. Following chemotherapy and radiation, preclinical and clinical results suggest that YIV-906 has the potential to improve the patient’s quality of life and prolonging survival. Consistent preparations of PHY906 could be manufactured apart 15 years. The effects of YIV-906 were studied on the anti-tumor activity of anti-PD1 using BDF1 mice bearing Hepa 1-6 tumors. Results indicated that anti-PD1 alone had moderate effects on tumor growth however YIV-906 plus anti-PD1 eradicated all tumors in all tumor bearing mice. Further re-implantation of Hepa 1-6 cells did not grow in the “cured” mice, but implanted CMT167 (non-small lung carcinoma) cells or Pan02 (Pancreatic Ductal Adenocarcinoma) cells did grow; suggesting that YIV-906 plus anti-PD1 created a tumor-specific vaccine-like effect. The combination treatment exhibited a highly inflamed tumor microenvironment with more M1-like macrophage expression over M2. In culture YIV-906 could potentiate the action of IFNg (interferon gamma) to polarize bone marrow-derived macrophages (BMDM) into M1 macrophages while inhibiting IL4 action for M2 macrophage polarization. YIV-906 potentiated IFNg action through: 1) stimulating IFNg secretion, 2) phosphorylation of JAK1/2 and STAT1 and 3) increasing IRF1 protein expression. Scutellaria baicalensis Georgi (S) and its flavonoids of YIV-906 were responsible for potentiate the IFNg to polarize macrophage into M1. In conclusion, YIV-906 enhanced the anti-tumor activity of anti-PD1 by enhancing inflammation in the tumor microenvironment and enriching M1-like macrophages. This suggests the potential use of combination YIV-906 and anti-PD1 in cancer treatment. This work was supported by grant (1PO1CA154295-01A1) from National Cancer Institute (NCI), NIH, USA. Dr. Yung-Chi Cheng is a fellow of National Foundation for Cancer Research (NFCR), USA. Citation Format: Wing Lam, Xiaochen Yang, Zaoli Jiang, Xue han, Fulan Guan, Rong Hu, Chang-Hua Xu, Wei Cai, William Cheng, Shwu-Huey Liu, Yuping Cai, Nicholas Rattray, Caroline Johnson, Lieping Chen, Yung-chi Cheng. YIV-906 (PHY906) enhanced the anti-tumor activity of immune checkpoint blockade therapy (Anti-PD1) against liver cancer by changing the tumor micro-environment associated with M1 macrophages infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2252.
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