Effects of P-MAPA Immunomodulator on Toll-like Receptors and ... · Effects of P-MAPA...

transcript

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

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)

• Chemical Analysis:

a) Protein: 0.5%, Molecular weight: 10

b) Phosphate: 45.2%;

c) Magnesium: 20.1%

d) Lipids: 11.6% of the total lipidis

e) Ammonium: 10.0%

What is P-MAPA?

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

Why the Study of Bladder Cancer is Important?

Histology of Urinary Bladder

Bladder Cancer: Types

• 70% of BC: superficial (NMIBC);

• 30% of BC: invasive (MIBC);

• NMIBC is classified into 3 stages: pTis, pTa and pT1

Tis Ta

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

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;

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

• 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.

P-MAPA Reverses the Histopathological Changes Induced by MNU

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.

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: wjfavaro@gmail.com

iseununes@gmail.com

Effects of P-MAPA Immunomodulator on Toll-like Receptors and ... · Effects of P-MAPA...

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