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NABIL HABIB INSTITUTE LebanusCedra Again… the Lebanese cedars www.nabilhabibinstitute.com APPENDIX 1. 2. 3. 4. 5. 6. INTRODUCTION MAIN CHARACTERISTICS FORMULA OF LEBANUS CEDRA HYDROXYSTEROL AND MODE OF ACTION WHO ARE WE? ASCO ABSTRACT Multidisciplinary Mediterranean Oncology Forum (MMOF/ESMO) ABSTRACT 7. DOCUMENTATION OF MMOF ABSTRACT 8. IMAGES OF PATIENTS RECEIVING LEBANUS CEDRA 9. PATENT CERTIFICATE AND CREDIT LETTERS FROM ALL OVER THE WORLD 10. BIBLIOGRAPHY www.nabilhabibinstitute.com 1. INTRODUCTION WHAT IS “LEBANUS CEDRA” ? “LEBANUS CEDRA” Is a cholesterol derivative (hydroxysterol). It is, to our knowledge, the only anticancer chemical with… Absolutely no side-effects www.nabilhabibinstitute.com 2. MAIN CHARACTERISTICS drug Many experiments performed in animal models have shown a remarkable antitumor activity on animal and human cancer cell-lines. No acute or chronic toxicity have been found in animals treated with 1000 x the doses used in humans. Hundreds of patients have been treated since 10 years and no side-effect have been observed with this drug. Its mode of action is original creating new avenues in the domain of cancer research. It is active in patients resistant and refractory to standard chemotherapies. Its mode of action is very fast; some tumors have been shown to regress within few days. Besides its anti-tumor activity, “Lebanus Cedra” has shown also a very rapid palliative effect in many patients, even in those who did not show a reduction of tumor size according to standard evaluation criteria for response to therapy. No interaction has been observed with other drugs and it seems (although we do not have a definitive proof of that), to promote the action of other anticancer drugs. www.nabilhabibinstitute.com 3. FORMULA of LEBANUS CEDRA and Mode of ACTION (24-ethyl-cholestane- 3β, 5α, 6α-triol) www.nabilhabibinstitute.com Mode of Action andAntineoplastic Activity: We believe that formula (I) compounds both inhibit the activity of HMG-CoA reductase, and competitively bind receptors involved in exogeneous colesterol adsorption. Inhibition of HMG-CoA 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 dioxideremoval 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 ., 24-ethyl-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-ethylcholestane- 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 three-dimensional 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. www.nabilhabibinstitute.com 4. 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’s Institute) 10 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” . www.nabilhabibinstitute.com 5. ASCO Abstract ASCO Home Meetings Abstracts 2009 ASCO Annual Meeting Antitumor activity of a new cholesterol derivative (24-ethyl-cholestane- 3β, 5α, 6α-triol) in solid tumors. Developmental Therapeutics: Cytotoxic Chemotherapy Meeting: 2009 ASCO Annual Meeting Abstract No:e13541 Citation: J Clin. Oncol. 27, 2009 (suppl; abstr e13541) Author(s): N. Habib, H. Daaboul, G. Hajj, A. Jabbour, N. Kassem; Bitar Hospital, Beirut, Lebanon Abstract: Oxysterols are oxygenated derivatives of cholesterol. They have nuclear receptors and have been shown to pass cell membranes and the blood-brain barrier at a faster rate than cholesterol itself. In addition, oxysterols have been ascribed a number of important roles in connection with cholesterol turnover, atherosclerosis, apoptosis, and necrosis. Oxysterols have been shown to have antitumor effects on experimental models. These compounds however may be toxic and to our knowledge, although some derivatives have been tested in animals, none have reached the clinical level. 24-ethyl-cholestane3β, 5α, 6α-triol is a new oxysterol developed in our lab. An oral form of this compound has been tested in mice and rats and has shown neither acute nor chronic toxicity. It has also been tested on animal tumor models and on human cancer xenografts. The results of these tests were very promising showing an anti-tumor activity on a panel of tumor cell lines. Our experiments on humans have shown no toxicity for this drug. Many patients with a variety of solid tumors all of whom have received many lines of chemotherapy and considered refractory to any conventional therapy have received this new drug. We observed in most of these patients a rapid and dramatic improvement in their quality of life and a fast pain control. Some patients could stop taking high doses of opioids within 1 or 2 days. A high rate of clinical benefit has also been observed in a variety of solid tumors including lung, breast, pancreatic, ovarian and uterine cancers, associated in some cases with a sharp decrease in tumor markers. Some patients with brain tumors (glioblastomas) have also responded to this therapy. www.nabilhabibinstitute.com 6. MMOF/ESMOABSTRACT 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 Oxygenated derivatives of cholesterol, oxysterols, have different physicochemical properties acting on cell membranes. Agents belonging to this class of compounds have been found to induce apoptosis and to harbor antitumor activity demonstrated in vitro and in vivo. 24-ethylcholestane- 3β, 5α, and 6α-triol are a new oxysterol developed in our lab. Unlike other derivatives, it is, to our knowledge, the first tested in the clinic. We have previously reported encouraging and rapid results observed in patients suffering from a variety of solid tumors with an improvement of their quality-of- life and without side- effects. We have treated six patients suffering from different types of sarcomas on a compassionate basis because we did not have any ongoing trial in sarcomas. Furthermore most of these patients would not have been eligible for a clinical trial because of their bad performance-status. Three patients were suffering from carcinosarcomas one from angiosarcoma, one from osteosarcoma and one from Ewing sarcoma. Most of them were pretreated with chemotherapy and radiotherapy and most of them were in a bad clinical condition. All the patients were females with ages ranging from 21 to 82 (median age 55y). None of these 6 patients experienced any side-effect despite the fact that one of them was taking a mild chemotherapy in association with oxysterol. This patient was excluded from the evaluation of the response to therapy. Among the 5 patients evaluable for response, we observed 4 complete responses (one of them confirmed by PET scan) and one progressive disease. The complete responses were observed in one osteosarcoma, one Ewing sarcoma, one angiosarcoma and one carcinosarcoma. As with our previous experience with this drug, no clinical or biological side-effect was observed and symptom control was achieved rapidly in most patients. We believe that this new compound deserves to be tested in a phase II trial setting in patients suffering from sarcomas. www.nabilhabibinstitute.com 7. DOCUMENTATION of PATIENTS in the MMOF Abstract Summary of Case Reports Case No 1: G.J. This is the case of a 70 YO female patient with a history of diabetes and hypertension. In Nov 2010, she was diagnosed with a carcinosarcoma of the uterus. She did not receive any therapy until end of December 2010. At that time a new work-up showed a pelvic tumor measuring 14 cm and a right suprarenal metastasis measuring 7cm and a lung nodule measuring 1.5 cm. She started her treatment with Lebanus Cedra on the 31 st of Dec 2010. A new work-up performed on the 16th of June 2011 shows a clearance of the pelvic mass and the suprarenal cystic mass is stable. Case No 2: H.M.H. This is the case of a 22 YO female Iraqi patient with no past medical history. In Dec 2006, she was diagnosed with a Ewing sarcoma of the right radius. She is treated with chemotherapy in India and with radiotherapy in Iran, followed by chemotherapy for a total of 12 courses. In 2008, a PET scan performed in India shows a right axillary adenopathy. She is operated in Iraq but unfortunately she has a new recurrence few months after. This axillary recurrence will be irradiated again in India in 2009 In May 2010, a PET scan shows a large recurrence in the right axillary area. The patient refuses to undergo a new chemotherapy. She started her treatment with Lebanus Cedra in June 2010. A new PET scan performed on the 8th of Nov 2010 shows a complete remission www.nabilhabibinstitute.com Case No 3 : N. N. This is a 59 YO female patient with no past medical history. In 2009, she is diagnosed with a poorly diff. carcinosarcoma of the uterus which is operated. She receives post op radiotherapy but in March 2011, she develops lung metastases She receives one course of combination chemotherapy (carboplatin and doxorubicin) but experiences a severe hematological and systemic toxicity. On the 8th of April 2011, she starts a treatment with Lebanus Cedra associated with a new chemotherapy with low doses of carboplatin and docetaxel. She is currently in good partial response. Case No 4: L.H. This 52 YO female patient has no past medical history In 2008, she is diagnosed with a poorly diff. thoracic carcinosarcoma which is operated and the patient receives post-op irradiation to the chest. In 2010, she develops a local recurrence and receives chemotherapy with gemcitabine and docetaxel without any success. From March to July 2011 she receives a treatment with Lebanus Cedra but unfortunately a work-up shows a progressive disease Case No 5 : R.M. This 21 YO female patient with no past medical history is diagnosed in August 2008 with an osteosarcoma of the maxillary sinus. She refuses standard therapy and is treated with herbs without success On the 19th of October 2000, she presents with a huge endo-buccal mass responsible of deglutition and respiratory problems. She is cachectic, dehydrated and asthenic. She starts a treatment with Lebanus Cedra. Few days after, her swallowing difficulties improve and her oral tumor starts to melt and to disintegrate. Her general condition improves also very quickly. A CT scan and a bone scan performed 3 months after show a complete remission www.nabilhabibinstitute.com Case No 6:M.B. This 82 YO female patient has a history of right breast cancer operated and irradiated. In May 2007, she is operated for a well differentiated (probably radio-induced) angiosarcoma of the right breast with skin invasion. In August 2008, she presents with lung metastases and severe dyspnea. She starts her treatment with Lebanus Cedra and one year after, she is in complete remission Summary of Patients‘Characteristics and Response Patient Age Type of sarcoma Response G.J 70 Carcinosarcoma CR H. H 22 Ewing Sarcoma N. N 59 Carcinosarcoma PR L. H 52 Carcinosarcoma PD R .M 21 Osteosarcoma CR M. B 82 Angiosarcoma CR CR www.nabilhabibinstitute.com +chemo 8. IMAGES OF PATIENTS’ RESPONSE TO LEBANUS CEDRA PATIENT WITH EWING SARCOMA PET scan BEFORE TREATMENT PET scan AFTER TREATMENT www.nabilhabibinstitute.com www.nabilhabibinstitute.com ANGIOSARCOMA OF THE LUNG Before treatment After treatment www.nabilhabibinstitute.com T SQUAMOUS-CELL CARCINOMA OF THE LUNG CHEST X-RAY BEFORE TREATMENT CHEST X-RAY AFTER TREATMENT CT-SCAN BEFORE THERAPY CT-SCAN AFTER THERAPY www.nabilhabibinstitute.com PATIENT WITH POORLY DIFFERENTIATED ADENOCARCINOMA OF THE LUNG CT-SCAN BEFORE THERAPY www.nabilhabibinstitute.com CT-SCAN AFTER THERAPY PATIENT WITH LARGE-CELL CARCINOMA OF THE LUNG WITH LIVER METASTASES CHEST CT-SCAN BEFORE THERAPY CHEST CT-SCAN AFTER THERAPY www.nabilhabibinstitute.com CT SCAN OF LIVER BEFORE THERAPY AFTER THERAPY www.nabilhabibinstitute.com BREAST CANCER AND BONE METASTASES BONE SCAN BEFORE THERAPY BONE SCAN AFTER THERAPY www.nabilhabibinstitute.com SQUAMOUS-CELL CARCINOMA OF THE TONGUE PET scan before treatment After treatment www.nabilhabibinstitute.com BREAST CANCER WITH BRAIN METASTASES Brain metastases before treatment Brain metastases after treatment Another case of Brain Metastases from a Breast Cancer Before treatment After treatment www.nabilhabibinstitute.com 9. PATENT CERTIFICATE and CREDIT LETTERS www.nabilhabibinstitute.com CREDIT LETTERS www.nabilhabibinstitute.com www.nabilhabibinstitute.com www.nabilhabibinstitute.com www.nabilhabibinstitute.com www.nabilhabibinstitute.com www.nabilhabibinstitute.com www.nabilhabibinstitute.com www.nabilhabibinstitute.com www.nabilhabibinstitute.com www.nabilhabibinstitute.com www.nabilhabibinstitute.com www.nabilhabibinstitute.com www.nabilhabibinstitute.com 10. BIBLIOGRAPHY: Antitumor activity of a new cholesterol derivative (24-ethyl-cholestane- 3β, 5α,6α-triol) 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 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. www.nabilhabibinstitute.com 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) Moog C; Frank N; Luu B; Bertram B Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg. www.nabilhabibinstitute.com