Effects of P-MAPA Immunomodulator on Toll-like Receptors and Angiogenesis: Potential Therapeutic Strategies For Non-Muscle Invasive Bladder Cancer

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UNIVERSITY OF CAMPINAS (UNICAMP) INSTITUTE OF BIOLOGY DEPARTAMENT OF STRUCTURAL AND FUNCTIONAL BIOLOGY Effects of P-MAPA Immunomodulator on Toll-like Receptors and Angiogenesis:

1 UNIVERSITY OF CAMPINAS (UNICAMP) INSTITUTE OF BIOLOGY DEPARTAMENT OF STRUCTURAL AND FUNCTIONAL BIOLOGY 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 1

2 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)

3 What is P-MAPA? 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% 3

4 What is P-MAPA? 4

5 Why the Study of Bladder Cancer is Important? 5

6 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 6

7 Why the Study of Bladder Cancer is Important? 7

8 Histology of Urinary Bladder 8

9 Bladder Cancer: Types 70% of BC: superficial (NMIBC); 30% of BC: invasive (MIBC); NMIBC is classified into 3 stages: ptis, pta and pt1 9

10 Tis Ta T1 10

11 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 11

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

12 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; 12

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14 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 14

15 Mechanism of Action of P-MAPA 15

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20 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. 20

21 Mechanism of Action of P-MAPA P-MAPA Reverses the Histopathological Changes Induced by MNU 21

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23 Mechanism of Action of P-MAPA 23

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Mechanism of Action of P-MAPA: Concluding Remarks 1- Interferon signaling pathway activation induced by P-MAPA led to

2- P-MAPA immunotherapy increased wild-type p53 protein levels.

3- Interferon signaling pathway induction and increased p53 protein levels by P-MAPA led to important antitumor

through suppression of angiogenesis, which was characterized by decreased VEGF and increased endostatin protein levels.

28 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. 28

29 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 29

30 Department of Structural and Functional Biology Avenida Bertrand Russel s/n. Anatomia (Bloco A) Contact: 30

Pharmacologyonline 3: (2006)

Pharmacologyonline 3: (2006) INTRAVESICAL MISTLETOE EXTRACT FOR ADJUVANT TREATMENT OF SUPERFICIAL URINARY BLADDER CANCER P. Bühler 1, C. Leiber 1, M. Lucht 2, P. Wolf 1, U. Wetterauer 1, U. Elsässer-Beile 1 1 Department of Urology,