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Effects of P-MAPA Immunomodulator on Toll-like
Receptors and Angiogenesis: Potential Therapeutic
Strategies For Non-Muscle Invasive Bladder Cancer
PROF. DR. WAGNER JOSÉ FÁVARO Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIM)
Member of Farmabrasilis
UNIVERSITY OF CAMPINAS (UNICAMP)
INSTITUTE OF BIOLOGY
DEPARTAMENT OF STRUCTURAL AND FUNCTIONAL BIOLOGY
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What is P-MAPA?
• P-MAPA is biopolymer produced by fermentation process from fungus
(A. oryzae);
• P-MAPA is a acronym for Proteinaceous Aggregate of Ammonium and
Magnesium Phospholinoleate-Palmitoleate Anhydride;
• Molecular weight: 320 kDa;
• Empirical formula: (C18H35Mg2NO21P5)373 (C326H614O163N204S2)
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• Chemical Analysis:
a) Protein: 0.5%, Molecular weight: 10
kDa;
b) Phosphate: 45.2%;
c) Magnesium: 20.1%
d) Lipids: 11.6% of the total lipidis
e) Ammonium: 10.0%
What is P-MAPA?
What is P-MAPA?
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Why the Study of Bladder Cancer is Important?
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Why the Study of Bladder Cancer is Important?
The American Cancer Society’s estimates for bladder cancer in the United
States for 2016 are:
• 76,960 new cases of bladder cancer (about 58,950 in men and 18,010 in
women)
• 16,390 deaths from bladder cancer (about 11,820 in men and 4,570 in
women)
The National Cancer Institute of Brazil’s estimates for bladder cancer in
this year are:
• 7,200 new cases of bladder cancer
• 3,000 deaths from bladder cancer
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Why the Study of Bladder Cancer is Important?
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Histology of Urinary Bladder
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Bladder Cancer: Types
• 70% of BC: superficial (NMIBC);
• 30% of BC: invasive (MIBC);
• NMIBC is classified into 3 stages: pTis, pTa and pT1
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Tis Ta
T1
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Bladder Cancer: Treatment
• For MIBC: total cystectomy associated to chemotherapy (Significant
Morbidity and Mortality;
• For NIMBC:
- Primary Treatment: TURBT
- TURBT + BCG Immunotherapy: pTa high-grade; pTis and pT1 low or
high grades;
- Since 1976: BCG is the best and the most effective NMIBC treatment;
- The response induced by BCG reflects induction of a T-helper type-1
response to prevent recurrence and to reduce tumor progression;
- BCG therapy shows several undesirable effects that are observed up to
90% of patients, such as fever, chills, fatigue, irritative symptoms,
haematuria and until major complications as sepsis and death
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Bladder Cancer: New Therapeutic Perspectives
• BCG use is limited in NMIBC by treatment failure, adverse effects and
intolerance that occur in over two-thirds of all patients;
• Almost 50% of patients will experience recurrence of their disease
within 4 years of their initial diagnosis, and 11% will progress to
muscle invasive disease;
• The P-MAPA immunomodulator appears as a valuable drug candidate
to play an important role in the treatment of NMIBC, presenting
therapeutic properties that are indicatives that this drug may be
superior to standard treatments available;
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Mechanism of Action of P-MAPA
• In a series of experiments performed in rats by our research group
using an appropriated animal model for the study of NMIBC, several
findings for the proposition of P-MAPA as drug candidate for treatment
of patients with NMIBC was found;
• Advantages of this animal model:
- Carcinogen (n-methyl-n-nitrosourea – MNU, a N-nitroso compound) is
administered directly in quantifiable pulse doses (4 doses – every
other week for 8 weeks) via intravesical;
- Low cost;
- Reproducibility: 100% of animals present NMIBC
- Immunocompetent host: very important when studying BCG treatment
and immunodulators;
- Very closely mimics human non-muscle invasive bladder cancer
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Mechanism of Action of P-MAPA
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Mechanism of Action of P-MAPA
• After MNU treatment (induction period), the animals were divided into 4
groups:
- Control group (negative control): received 0.30 ml of 0.9%
physiological saline;
- MNU group (Cancer group): received 0.30 ml of 0.9% physiological
saline;
- MNU-BCG group: received 40 mg of BCG;
- MNU-P-MAPA group: received 5 mg/kg dose of P-MAPA;
- All animals were treated for 6 consecutive weeks;
• After treatment with BCG and P-MAPA, the animals were sacrificed and
samples of urinary bladder were submitted to histopathological and
molecular analyses.
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Mechanism of Action of P-MAPA
P-MAPA Reverses the Histopathological Changes Induced by MNU
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Mechanism of Action of P-MAPA
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Mechanism of Action of P-MAPA
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Mechanism of Action of P-MAPA: Concluding
Remarks
1- Interferon signaling pathway activation induced by P-MAPA led to
increase of iNOS protein levels, resulting in apoptosis and
histopathological recovery.
2- P-MAPA immunotherapy increased wild-type p53 protein levels. The
increased wild-type p53 protein levels were fundamental to NO-induced
apoptosis and the up-regulation of BAX.
3- Interferon signaling pathway induction and increased p53 protein levels
by P-MAPA led to important antitumor effects, not only suppressing
abnormal cell proliferation, but also by preventing continuous expansion
of tumor mass through suppression of angiogenesis, which was
characterized by decreased VEGF and increased endostatin protein
levels.
4- P-MAPA immunotherapy could be considered an important therapeutic
strategy for NMIBC, as well as, opens a new perspective for treatment of
patients that are refractory or resistant to BCG intravesical therapy.
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What is FARMABRASILIS?
• Non-governmental, nonprofit research network;
• Since 1987: American and European scientists and people devoted to
the research and development of new medicines and technologies;
• Apply to economically disadvantaged populations and individuals
affected by cancer and neglected diseases;
• Farmabrasilis is responsible to development of P-MAPA
immunomodulator;
• P-MAPA licensing policy includes the possibility of royalty-exempt
production by public (Brazil) in the cases of cancer (non-muscle
invasive bladder cancer);
• Regulatory: FDA application underway
Department of Structural and Functional Biology
Avenida Bertrand Russel s/n.
Anatomia (Bloco A)
+55 19-35216308
Contact: [email protected]
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