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EUROPEAN SOCIETY of CLINICAL ONCOLOGY (ESMO) Madrid 2014 Lebanus Cedra LebanusCedra ABSTRACT 954 P A new non-chemo and non-toxic drug (24-ethyl-cholestane- 3β,5α,6α-triol ) with antitumor activity in advanced refractory or recurrent, mainly aggressive non-Hodgkin lymphomas. N. Habib; H. Daaboul; G. Hage. A. Jabbour. N. Kassem and. R. Khalifeh. Nabil Habib Institute Beirut. LEBANON Oxysterols are oxygenated derivatives of cholesterol. Some of these compounds may be toxic and even oncogenic while others seem promising as anticancer drugs. Advanced recurrent or refractory non-Hodgkin lymphomas (NHLs) have a dismal prognosis and are treated palliatively. (24-ethyl-cholestane- 3β,5α,6α-triol) is an oxysterol developed by our group. Besides its high antitumor potential, it has been shown to be devoid of side-effects. From 2001 to 2013 we have treated 14 patients (pts) suffering from relapsed or refractory Non-Hodgkin lymphomas. Eight were males and 6 females. The median age was 50y. Eight of these pts were suffering from diffuse large B-cell lymphomas, 2 from lymphoplasmacytic lymphomas, 1 maltoma, 1 diffuse mixed, 1 anaplastic and 1 large T-cell lymphoma. Five pts were stage II (one was 2EB), 4 were stage III and 5 stage IV. Nine pts had B symptoms and 8 other symptoms (pain, neurologic symptoms, dyspnea…) . Except 2 pts, all had previously received 2 to 3 chemotherapy regimens and 5 pts had been treated with radiotherapy. Most of them had a poor PS. Patients received daily 10 mg/Kg of oral (24-ethyl-cholestane- 3β,5α,6α-triol) divided in 3 equal doses, every until disease progression. Five patients exhibited a complete remission (CR), 3 pts had a partial remission (PR) 4 pts had a stable disease (NC) and 2 pts progressed under treatment. The median follow-up was 3 years. Most of the pts experienced a rapid (within few days) and dramatic improvement in their quality of life and a fast and remarkable all-symptoms control. Some patients taking high doses of pain-killers and or opioids could stop them within 2-4 days. No side-effects of any kind were observed. Conclusion: According to these excellent results, (24-ethyl-cholestane- 3β,5α,6α-triol) seems to be a good candidate for phase II trials in NHLs with or without concurrent chemotherapies or targeted therapies. www.nabilhabibinstitute.com EUROPEAN SOCIETY of CLINICAL ONCOLOGY (ESMO) Madrid 2014 INTRODUCTION “LEBANUS CEDRA” Is a cholesterol derivative (hydroxysterol). It is, to our knowledge, the only anti-cancer chemical with: Absolutely no side-effects MAIN CHARACTERISTICS • Many experiments performed in animal models have shown a remarkable anti-tumor activity on animal and human cancer cell-lines. TERISTICS “LEBANUS CEDRA” • No acute or chronic toxicity have been found in animals treated with 1000 x the doses used in humans. Is a• cholesterol derivativeperformed (hydroxysterol). It is, to our have knowledge, the only antiexperiments in animal shown a side• Many Hundreds of patients have been treatedmodels since 10 years and no cancer chemical with… remarkable anti-tumor activity animal effect have been observed withonthis drug.and human cancer cell-lines. •• No acute of or action chronicis toxicity beennew found in animals with Its mode originalhave creating avenues in thetreated domain of 1000 x the doses used in humans. cancer research. •• Hundreds been treated sinceto10standard years and no sideIt is active of in patients patients have resistant and refractory effect have been observed with this drug. chemotherapies. •• Its creating new avenues in the domain of Its mode mode of of action action is is original very fast; some tumors have been shown to regress cancer research. within few days. •• It is active patients resistant and refractory to standard Besides itsinanti-tumor activity, “Lebanus Cedra” has shown also a very chemotherapies. rapid palliative effect in many patients, even in those who did not show a • reduction Its mode of very fast; some tumors have been shown regress ofaction tumor is size according to standard evaluation criteriatofor within fewto days. response therapy. • Besides its anti-tumor activity, “Lebanus Cedra” hasand shown also a very No interaction has been observed with other drugs it seems www.nabilhabibinstitute.com rapid palliative in many patients,proof evenofinthat), thosetowho did not a (although we doeffect not have a definitive promote theshow action reduction of tumor size according to standard evaluation criteria for of other anti-cancer drugs. Absolutely no side-effects EUROPEAN SOCIETY of CLINICAL ONCOLOGY (ESMO) Madrid 2014 WHO ARE WE? Doctor Nabil Habib is a PhD in chemical Engineer teaching at the Lebanese University. He has a prestigious curriculum and has achieved great and patented inventions in different fields of the industry and public health. He trained in France and has performed collaborative researches with scientists in the USSR as well as in the USA. He launched his research on anti-cancer drugs fifteen years ago. He created his own medical center (Nabil Habib Institute) 15 years ago and with the collaboration of a team of physicians and medical oncologists, is helping desperate cases of terminal cancer patients trying to improve their quality of life and fight their cancer without causing any side effect with his new and revolutionary molecule e.g Hydroxysterol, alias “Lebanus Cedra”. FORMULA of LEBANUS CEDRA (24-ethyl-cholestane- 3β, 5α,6α-triol) www.nabilhabibinstitute.com EUROPEAN SOCIETY of CLINICAL ONCOLOGY (ESMO) Madrid 2014 Mode of Action-Antineoplastic Activity: We believe that formula (I) compounds both inhibit the activity of HMG-CoA reductase, and competitively bind receptors involved in exogeneous cholesterol adsorption. Inhibition of HMGCoA reductase occurs in both normal cells and neoplastic cells; however, neoplastic cells are additionnally rendered unable to adsorb exogeneous cholesterol following administration of formula (I) compound. This selectivity for neoplastic cells occurs for two reasons. First, tumors are poorly vascularized, which leads to a reduced supply of available exogeneous cholesterol. Second, the reduced vascularization additionnally leads to hypoxia, thereby increasing the concentration of anaerobic metabolic products, pyruvic acid and carbon dioxide. Further, poor vascularization decreases the rate of carbon dioxide removal from the tumor tissue. Increased levels of carbon dioxide, in turn, leads to increased levels of carbonic acid, the formation of which is catalyzed by carbonic anhydrase. These factors reduce the pH of the environnment surrounding the cells from a pH of 7.3-7.4, found in normal cells to pH 6.4-6.8. The lower pH environnment in neoplastic cells causes the administered formula (I), e.g ., 24ethyl-cholestane- 3β, 5α,6α-triol, to migrate towards intercellular interstitial acidic fluid, and also increases the affinity of 24-ethyl-cholestane- 3β, 5α,6α-triol for the cholesterol receptors. This increased affinity, in combination with the reduced cholesterol concentration present in the fluid surrounding tumor cells, leads to specific, irreversible binding of the compound to the receptor. In the case of 24-ethyl-cholestane- 3β, 5α, 6α-triol, binding is mediated by the three highly hydrophilic hydroxyl groups interacting with carbonyl groups of the receptor. The position s3β, 5α, 6αhydroxides further provoke distortion of the membrane layers, and the ethyl group at position 24 plays the role of a “check valve”, fixing the hydrophobic tail between the two lipid layers. In addition to binding the receptors directly, 24-ethyl-cholestane- 3β, 5α, 6α-triol alters the threedimensional structure of remaining unbound cholesterol receptors through distortion of the lipid bi-layer. This alteration is sufficient to prevent adsorption of cholesterol molecules. This distortion of the lipid bi-layer has other effects as well. The permeability and the fluidity of the bi-layer membrane are also reduced, thus decreasing passive, mediated and active diffusion across the membrane. This alteration can further decrease the nutritional level of tumor cells. This will lead to cell turgescency and induce apoptosis. www.nabilhabibinstitute.com EUROPEAN SOCIETY of CLINICAL ONCOLOGY (ESMO) Madrid 2014 www.nabilhabibinstitute.com EUROPEAN SOCIETY of CLINICAL ONCOLOGY (ESMO) Madrid 2014 Summary of Patients‘ Characteristics Patients Sex Age Pathology Stage Previous therapies 2EB IV IIB 2EB IIA IVB IIIA IV II IV IIIA IV IIIA IIIA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 M F F F M F M M F M M F M M 55 67 81 28 38 79 52 78 43 50 64 71 56 63 DLBCL DLBCL DLBCL Anaplastic Maltoma Diffused mixed Large T-‐cell lymphoplasmacytic lymphoplasmacytic DLBCL DLBCL DLBCL DLBCL DLBCL M/F: 8/6 Med.Age: 50 Stages: 5II, 4III, 5 IV All heavily pretreated except 2 DLBC: Diffuse Large B-cell lymphoma www.nabilhabibinstitute.com + Rϴ 3 2 0 2 2 + Rϴ 2 0 3 + Rϴ 1 2 + Rϴ 3 2 3 2+ Rϴ EUROPEAN SOCIETY of CLINICAL ONCOLOGY (ESMO) Madrid 2014 Patients‘ Response and Time to Progression Patients Time to Follow-‐up Response 1 2 3 4 5 6 7 8 9 10 11 12 13 14 CR CR PR CR CR CR PR PR PR PR NC PG PG NC Responses: 5CR, 3PR, 4NC, 2Pg 12 y 3y 1y lost 9m 4y 5y 1y lost 3y lost 3y 1Y 2y 6m 1y 2y Time to Follow-up (median): 3y www.nabilhabibinstitute.com EUROPEAN SOCIETY of CLINICAL ONCOLOGY (ESMO) Madrid 2014 References : • A cholesterol derivative (oxysterol; 24-ethyl-cholestane-3β, 5α, 6α-triol) with high antitumor activity against a variety of sarcomas Nabil Habib, Hamid Elia Daaboul, Georges Hage, Abdo Jabbour, Riad Khalife, Nader Kassem; . J Clin Oncol 30, 2012 (suppl; abstr e20500) Nabil Habib Institute, Beirut, Lebanon • An Oxysterol (24-ethyl-cholestane- 3β, 5α, 6α-triol) with high antitumor activity against a variety of sarcomas. N. Habib; G. Hajj. H. Daaboul. R. Khalifeh and A. Jabbour; Bitar Hospital. Sabtieh.Sadd El Baouchrieh. Lebanon . MMOF/ESMO Istambul 2011 • Antitumor activity of a new cholesterol derivative (24-ethyl-cholestane- 3β, 5α,6αtriol) in solid tumors. Habib N;Daaboul H; Hajj G; Jabbour A;Kassem N; ASCO Abstract No: e13541 Citation: J ClinOncol 27, 2009 (suppl; abstr e13541) Bitar Hospital, Beirut, Lebanon • Natural products reveal cancer cell dependence on Oxysterol-binding proteins. Nature Chemical Biology 7, 639-647 (2011) doi: 10. 1038/nchembio.625 Burgett AWG; Poulsen TB; Wangkanont K; Anderson R; Kikuchi C • Oxysterols: friends, foes, or just fellow passengers? ArteriosclerThrombVasc Biol. 2002; 22(5):734-42 (ISSN: 1524-4636) Björkhem I; Diczfalusy U Division of Clinical Chemistry, KarolinskaInstitutet, Huddinge University Hospital, Huddinge, [email protected] • On the efficacy and safety of combination Ezetimibe plus statin therapy . ClinLipidology. 2010; 5 (5) 655-684, Future Edicine Toth PP; Catapano A; Tomassini • Synthesis and anticancer evaluation of certain indolo[2,3-b]quinoline derivatives. Bioorg Med Chem. 2004; 12(24):6539-46 (ISSN: 0968-0896) Chen YL; Hung HM; Lu CM; Li KC; Tzeng CC Faculty of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical www.nabilhabibinstitute.com EUROPEAN SOCIETY of CLINICAL ONCOLOGY (ESMO) Madrid 2014 References Cont: • Structures of biologically active oxysterols determine their differential effects on phospholipid membranes. Biochemistry. 2006; 45(35):10747-58 (ISSN: 0006-2960) Massey JB; Pownall HJ Section of Atherosclerosis and Lipoprotein Research, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. [email protected] • Analysis of oxysterols by electrospray tandem mass spectrometry J Am Soc Mass Spectrom. 2006; 17(3):341-62 (ISSN: 1044-0305)Griffiths WJ; Wang Y; Alvelius G; Liu S; Bodin K; Sjövall J Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, London, United Kingdom. • Role of oxysterol structure on the microdomain-induced microsolubilization of phospholipid membranes by apolipoprotein A-I. Biochemistry. 2005; 44(43):14376-84 (ISSN: 0006-2960) Massey JB; Pownall HJ Section of Atheroscler Steroids. 2003; 68(3):221-33 (ISSN: 0039-128X) Adiposis and Lipoprotein Research, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. [email protected] • Chromatographic behavior of oxygenated derivatives of cholesterol. Steroids. 2003; 68(3):221-33 (ISSN: 0039-128X) Shan H; Pang J; Li S; Chiang TB; Wilson WK; Schroepfer GJ Department of Biochemistry and Cell Biology, Rice University, MS 140, 6100 Main Street, Houston, TX 77005-1892, USA. • Cytotoxic properties of a phosphoglycoconjugated derivative of 7 beta-hydroxycholesterol upon normal and tumor cells in culture. AnticancerRes. 1997; 17(4A):2621-6 (ISSN: 0250-7005) Hyun JW; Weltin D; Holl V; Marchal J; Dufour P; Luu B; Bischoff P Laboratorie de Chimie Organique des Substances Naturelles, ULP associé CNRS, Strasbourg, France. • Metabolism of new anticancer oxysterol derivatives in rats. Anticancer Res. 1993; 13(4):953-8 (ISSN: 0250-7005) www.nabilhabibinstitute.com EUROPEAN SOCIETY of CLINICAL ONCOLOGY (ESMO) Madrid 2014 Moog C; Frank N; Luu B; Bertram B Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg. www.nabilhabibinstitute.com