Download Lebanus Cedra LebanusCedra

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