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Mechanisms and effects of the immunomudolator P-MAPA in the treatment of prostate and non-muscle invasive bladder cancer-interfaces among energetic metabolism, oxidative balance, angiogenesis and toll-like receptors pathways

Grant number: 14/12047-4
Support Opportunities:Regular Research Grants
Start date: April 01, 2015
End date: March 31, 2017
Field of knowledge:Health Sciences - Medicine - Surgery
Principal Investigator:Wagner José Fávaro
Grantee:Wagner José Fávaro
Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated researchers:Alexandre Gabarra de Oliveira ; Andrey dos Santos ; Athanase Billis ; Patrick Vianna Garcia ; Petra Karla Böckelmann ; Roger Chammas

Abstract

Understanding how cancer cells are able to ensure a positive energetic balance and associate it with anabolic processes is vital to the development of effective therapies against cancer. The neoplastic cells face two major challenges: answer the bioenergetic and biosynthetic demands of increased growth and cellular proliferation and implement metabolic adaptation strategies to survive the environmental fluctuations of nutrients and oxygen when tumor growth exceeds the supply capacity of the existing vascular nets. The oxygen uptake by tumor cells may be directly related to the generation of reactive oxygen species (ROS) since they are normally produced at low levels during the process of cellular respiration. Thus, studying the association of prostate cancer (PCa) and non-muscle invasive bladder cancer (NMIBC) with ROS, angiogenesis and energetic metabolism is crucial to understand these tumors and how such events differ from normal conditions of the cell. Another important point is to study the interaction of different therapeutic approaches with the modulation of the immune system through the signaling pathway of Toll-like receptors (TLRs) 2 and 4. Thus, compounds able to act as TLRs agonists may be promising candidates to be developed as anticancer drugs. In this scenario, the immunomodulator P-MAPA opens a new perspective against some types of cancer, including PCa and NMIBC due to its versatility and minimal cytotoxicity. Studies from our group (Laboratory of Carcinogenesis and Urogenital Immunotherapy/UNICAMP) demonstrated that in vivo treatment of PCa and NMIBC with P-MAPA significantly reduces the tumor, indicating an antitumor effect of this immunomodulator. The multifactorial nature of angiogenesis in malignant tumors suggests that the combination of antiangiogenic drugs with agents that modulate the immune system, the cellular metabolism as well as pro- and antioxidant species may be more effective than therapies with a single agent. Therefore, the association between P-MAPA and TNP-470 (an angiogenesis blocker) may be considered a promising therapeutic strategy against PCa and NMIBC. The need for new drugs or drug combinations is due to the high recurrence of PCa and NMIBC. In NMIBC, the immunotherapy with BCG still is the most effective strategy to prevent tumor progression and recurrence. However, immunotherapy with BCG is often associated with local and/or systemic side effects, including sepsis and tumor recurrence in up to 31% of cases. In PCa, several studies have been conducted to provide new therapeutic options, namely antiangiogenic agents, inhibitors of cell signaling pathways involved in growth and apoptosis, analogs of vitamin D cytotoxic agents and antisense oligonucleotide-based therapy. However, we still cannot fully verify the effectiveness of these therapies because many of them are high-cost which in practice restricts its use by the health system in Brazil (SUS). Thus, it is relevant to study and develop new therapies against PCa and NMIBC which are supposed to be more efficient, to have lower side effects and to be produced from local technology, enabling them to be used by SUS due to its low cost. Furthermore, several studies have demonstrated increased risk for simultaneous occurrence of PCa and NMIBC and also the existence of a possible molecular association between them, so that the clinical implications of this association are potentially significant. Thus, the objectives of this project are to characterize and compare the immune, histopathological, molecular and biochemical effects of antiangiogenic therapy (TNP-470) in combination with P-MAPA in the treatment of chemical induced PCa and NMIBC in rats. Also, we aim to establish the possible mechanisms of action of these therapies regarding energetic metabolism, oxidative balance, angiogenesis and TLRs pathways. Furthermore, we intend to investigate the occurrence of common mechanisms for carcinogenesis of the prostate and urinary bladder. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
QUEILA CRISTINA DIAS; ISEU DA SILVA NUNES; PATRICK VIANNA GARCIA; WAGNER JOSÉ FÁVARO. Potential therapeutic strategies for non - muscle invasive bladder cancer based on association of intravesical immunotherapy with P-MAPA and systemic administration of cisplatin and doxorubicin. INTERNATIONAL BRAZ J UROL, v. 42, n. 5, p. 942-954, . (14/12047-4)