BACKGROUNDThe natural compound triptolide has been shown to decrease cell proliferation and induce apoptosis and cellular senescence. We previously demonstrated that triptolide decreases tumor formation and metastasis of human non-small cell lung cancer cells (NSCLC). Due to the toxicity of triptolide, derivatives of the natural compound have been developed that show more favorable toxicity profiles and pharmacokinetics in animal models. The purpose of this study was to evaluate MRx102 as a novel therapeutic for lung cancer.METHODSMice injected subcutaneously with H460 lung cancer cells were treated with MRx102 or carboplatin to determine the effect of MRx102 on tumor formation in comparison to standard treatment. Patient-derived xenografts (PDX) with different WIF1 expression levels were treated with MRx102 or cisplatin. We tested the effects of MRx102 treatment on migration and invasion of lung cancer cells using Transwell filters coated with fibronectin and Matrigel, respectively. Tail vein injections using H460 and A549 cells were performed.RESULTSHere we report that the triptolide derivative MRx102 significantly decreases NSCLC proliferation and stimulates apoptosis. Further, MRx102 potently inhibits NSCLC haptotactic migration and invasion through Matrigel. In vivo, NSCLC tumor formation and metastasis were greatly decreased by MRx102 treatment. The decrease in tumor formation by MRx102 in the patient-derived xenograft model was WIF1-dependent, demonstrating that MRx102 is a potent inhibitor of the Wnt pathway in low WIF1 expressing NSCLC patient tumors.CONCLUSIONSThese results indicate that MRx102 has potent antitumor effects both in vitro and in vivo, and is a potential novel therapy for the treatment of NSCLC.

18 Nov 2011·Blood

MRx102, a Novel Triptolide Analogue, Has Low Nanomolar Activity Against AML Stem/Progenitor Cells in Vitro and in a Murine Model of AML

Author: Plunkett, William ; Shi, Yuxie ; Andreeff, Michael ; Ling, Xiaoyang ; Mak, Duncan H ; Chen, Rong ; Fidler, John M. ; Carter, Bing Z

AbstractAbstract 1547Current chemotherapeutic regimens are known to be ineffective against AML stem/progenitor cells that is responsible for disease relapses due to both intrinsic resistance of these cells and extrinsic environmental factors. Triptolide, isolated from the herb Tripterygium wilfordii, has been shown to potently inhibit growth and induce apoptosis in various malignant cells by inhibiting RNA synthesis and NF-κB activity. Previously, we showed that triptolide promotes apoptosis in AML cells via the mitochondria-mediated pathway, in part by decreasing levels of the anti-apoptotic proteins XIAP and Mcl-1. MRx102 is a novel triptolide derivative, acting by converting to triptolide. We investigated whether MRx102 effectively targets primary human AML cells, particularly AML stem/progenitor cells co-cultured with bone marrow (BM) derived mesenchymal stromal cells (MSCs), and examined the effects of MRx102 in NOD/SCID mice injected with Ba/F3-ITD cells. We show here that MRx102 potently promoted apoptosis in AML cell lines, with EC50 values of low nanomolars for OCI-AML3 and MV4-11 cells. Like triptolide, MRx102 decreased XIAP and Mcl-1 protein levels and inhibited RNA synthesis in OCI-AML3 cells. Interestingly, we also found that MRx102 and triptolide decreased β-catenin protein level in OCI-AML3 cells. MRx102 effectively induced apoptosis in all primary AML samples tested, regardless of the cytogenetics or clinical responses to various therapies of the patients at the time of sampling (ED50 = 132.1 ± 7.5 nM, n=12) and was less toxic to normal BM cells (ED50 = 209.9 ± 56.8 nM, n=3). In addition to bulk AML cells, MRx102 also induced apoptosis in CD34+ progenitors, and more importantly in CD34+CD38− stem/progenitor cells from AML patients, even when they were protected by co-culturing with BM-derived MSCs. The effectiveness of MRx102 on AML stem/progenitor cells may be in part due to its ability to decrease β-catenin and triptolide's ability to inhibit NF-κB activity as both Wnt/β-catenin and NF-κB are highly active in AML stem/progenitor cells. Furthermore, in vivo, MRx102 greatly decreased leukemic burden, reduced infiltration of leukemic cells to various organs, and increased survival of NOD/SCID mice harboring Ba/F3-ITD cells (median survival 43 days with MRx102 at 3.0 mg/kg/day compared with 36 days for the untreated mice, P = 0.027).Collectively, we demonstrated that MRx102 has strong antileukemic activity both in vitro and in vivo in a murine model of AML, has the potential to eliminate AML stem/progenitor cells and overcome microenvironmental protection of leukemic cells, and warrants clinical investigation.Disclosures:Fidler: MyeloRx LLC: Employment.

19 Nov 2010·Blood

Preclinical Development of Triptolide Derivative MRx102 as a Therapeutic Agent for Acute Myeloid Leukemia

Author: Mak, Duncan H. ; Musser, John H. ; Andreeff, Michael ; Fidler, John M. ; Carter, Bing ; An, Jinhua

AbstractAbstract 3271Acute Myeloid Leukemia (AML) is the most common form of adult acute leukemia and the second most common childhood leukemia. AML has the lowest survival rate among leukemias, and the frequency is increasing as the population ages. Current therapies are inadequate, and a need exists for better therapeutic agents to treat AML, both as initial treatment for newly diagnosed patients and for those who have failed current therapy and relapsed. Natural products, such as taxol, have shown activities in a variety of disease states, including cancer. Triptolide is a natural product diterpenoid derived from Tripterygium wilfordii Hook f, and has shown anti-cancer activity in a broad range of solid tumors in preclinical models. It induces apoptosis in various leukemic cell lines and primary AML blasts (Carter, B et al, Blood 2006). Derivatives of triptolide with improved pharmacokinetics and bioavailability offer the opportunity to optimize the activity of triptolide for clinical application in AML. MRx102 is a triptolide derivative that is more hydrophobic than triptolide. It has potent in vitro cytotoxic activity with human tumor and leukemia cell lines, an unusual result for triptolide derivatives because they are usually much less active in vitro than the parent compound. Designed as a prodrug, MRx102 exerts cytotoxic activity with human AML cell lines and other human leukemia cell lines without pre-incubation with plasma esterases (IC50 of 51.0 and 37.1 nM with MV4-11 AML cells at 48 and 72 hours, respectively, ∼55% and ∼36% of the activity of triptolide, respectively). MRx102 decreases the viable CD34+ blasts of AML patient samples (a mean of 79.8 ± 8.8% specific apoptosis at 100 nM, n=3), and overcomes the apoptosis protection by co-cultivated stromal cells (with a similar mean of 74.1 ± 8.5%). MRx102 shows dose-dependent anti-tumor activity with the MV4-11 cell line in nude mouse human AML tumor xenografts. After 42 days of MRx102 dosing at 1.35 mg/kg/day i.p., tumor volume was inhibited by 99.7%. Tumors removed from several mice appeared to be Matrigel pellets rather than vascularized tumors, suggesting that many of the tumors were completely eliminated. In studies with the OCI-AML3 human AML cell line xenograft model, the group receiving MRx102 at 1.35 mg/kg/day i.p. showed similar high activity, with mean tumor volume reduced by as much as 99.2% on day 23 compared to the vehicle control group. Tumors of 7 of 10 mice were smaller than the day 0 volumes at the day 28 end of the study. As part of drug development, toxicology testing with MRx102 was initiated with an acute single dose rat toxicology study with no deaths and no adverse signs up to the top dose of 3.0 mg/kg MRx102 in DMSO/PBS administered i.v. The maximum tolerated dose (MTD) is greater than 3 mg/kg of MRx102, and the no observable adverse effect level (NOAEL) is at least 3 mg/kg. A 7-day subacute rat toxicology study of MRx102 showed no deaths and no adverse signs up to the top dose of 1.5 mg/kg/day MRx102 in DMSO/PBS administered daily i.v. for 7 days. The histopatholgy report shows no findings related to administration of the test article. The MRx102 MTD is greater than 1.5 mg/kg/day, and the NOAEL is at least 1.5 mg/kg/day. Previously observed NOAELs for related compounds have been less than 0.1 mg/kg/day. The current studies show potent anti-tumor activity as well as an unusually positive safety profile for MRx102 when compared to triptolide and other triptolide derivatives. Further MRx102 drug development is underway, with the intention of submitting an Investigational New Drug application to the Food and Drug Administration leading to clinical evaluation of MRx102 in AML patients. Updated results on current drug development activities will be presented at the meeting. This work is supported in part by NCI SBIR Contract HHSN261200900061C to MyeloRx LLC.Disclosures:Fidler: MyeloRx LLC: Employment, Equity Ownership, PI for an NCI Contract to MyeloRx LLC, Patents & Royalties. An:MyeloRx LLC: Employment, Equity Ownership, participant in research under an NCI SBIR Contract to MyeloRx LLC. Musser:MyeloRx LLC: Employment, Equity Ownership, Patents & Royalties, participant in research under an NCI SBIR Contract to MyeloRx LLC. Mak:MyeloRx LLC: participant in research under an NCI SBIR Contract to MyeloRx LLC. Carter:MyeloRx LLC: participant in research under an NCI SBIR Contract to MyeloRx LLC. Andreeff:MyeloRx LLC: Consultancy, participant in research under an NCI SBIR Contract to MyeloRx LLC.

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Drug(Targets)	Indications	Global Highest Phase

MRx-102 ( DNA helicase )	Adult Acute Myeloblastic Leukemia More	Phase 2
MRx-104	-	Discontinued
MRx-103	Neoplasms More	Discontinued
MRx-109	Graft Rejection More	Pending

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