13/05/2017

Animal models of cancer - bladder cancer

•  Effects of P-MAPA on urinary bladder cancer

Overview

Bladder cancer treatment is still a challenge. The standard of care for bladder cancer has presented few changes over the last decades, and treatment options remain limited. Some treatments, such as cystectomy, imply drastic lifestyle changes that diminish the patients quality of life while falling far short of achieving cure.

The standard conservative treatments - surgical resection of urinary bladder followed by intravesical Bacillus Calmette-Guèrin (BCG) immunotherapy - avoid the progression of high-grade non-muscle invasive bladder cancer (NMIBC) to advanced disease, but often the efficacy is weakened by the emergence of refractory or relapsing disease, and toxicity causes the discontinuation of the treatment.

Radical or partial cystectomy is the option for non-responsive patients to the current bladder-sparing therapies. Patients who refuse or are not eligible for bladder removal face a dismal prognosis, due to the increased risk of progression to advanced disease. Despite conservative treatments, a large number of NMIBC patients at the time of diagnosis will develop invasive or metastatic disease.

Around half of patients with locally advanced or metastatic bladder cancer do not respond satisfactorily to first-line platinum-based chemotherapies, that is, methotrexate, vinblastine, doxorubicin (adriamycin) and cisplatin (MVAC), and gemcitabine and cisplatin (GC). Due to cisplatins high toxicity, many patients will receive doses lower than those typically recommended or even no treatment. The alternative would be a carboplatin-based chemotherapy, as second-line treatment (gemcitabine plus carboplatin or gemcitabine plus paclitaxel), which provides a median survival of 9-10 months.

Despite the first-line platinum-based therapy, options are quite few for those patients whose malignant lesions progress. Only 10% to 15% of them respond to second-line single-agent chemotherapy. The recently approved immune checkpoint inhibitors seem to be a promising alternative to treat patients with advanced and metastatic bladder cancer who fail or are ineligible for first-line platinum-based chemotherapies, but the treatment has presented limitations due to toxicity and lack of effectivity for some patients.

In summary, conservative treatments provide a far from ideal solution for large groups of NMIBC patients and there is a huge need for bladder cancer therapies that really work.

P-MAPA - an antitumor compound in late-stage development, could be one of them. P-MAPA can help to reach the best therapeutic strategy in the treatment of bladder cancer blocking the cancer process still in the urinary bladder with a bladder preservative approach, so avoiding the progression of the disease.  

Based on preclinical studies carried out over the last years, intravesical P-MAPA immunotherapy represents a novel approach to fight high-grade malignant lesions still in the urinary bladder, before they spread to adjacent tissues and organs.

Experimentally, P-MAPA has shown an impressive antitumor activity and a clear superiority over BCG, in comparative studies of efficacy and safety. As evidenced in animal models for study of bladder cancer, P-MAPA can help to overcome the BCGs lack of effectivity and high toxicity for large groups of patients. The toxicity of P-MAPA in the urothelium at therapeutic dosage is close to zero.

Under a bladder-sparing approach, P-MAPA could be used to treat NMIBC patients who are BCG-refractory, BCG relapsing and BCG-intolerant, as well as the refractory ones to approved second-line intravesical therapy, eliminating malignant lesions before they spread to other tissues and organs. Notably, as preclinical studies have evidenced, P-MAPA could also be used in the treatment of the advanced forms of the disease, in association with other drugs, without additional toxicity. 

The five specific conditions in which P-MAPA could be used, helping to solve unmet medical needs, are:

● Condition 1: Patients with high-grade non-muscle invasive bladder cancer (NMIBC) at high risk of recurrence and disease progression who are BCG-refractory or BCG relapsing.

● Condition 2: Patients with high-grade NMIBC at high risk of recurrence and disease progression who are BCG-intolerant.

● Condition 3: Patients with high-grade NMIBC who are BCG-refractory or BCG relapsing, for whom cystectomy would be associated with high morbidity or mortality.

●  Condition 4: Patients with high-grade NMIBC, BCG-refractory and BCG-relapsing, at high risk of recurrence and progression, for whom cystectomy would be associated with high morbidity or mortality, and who are refractory to Valrubicin as second-line therapy.

● Condition 5: Patients with locally advanced and metastatic bladder cancer.

See the full scientific rationale at: P-MAPA SCIENTIFIC RATIONALE

 Additional information 

● Hyperlinks to PubMed for P-MAPA

● Bladder cancer

2012

Effects of P-MAPA Immunomodulator on Toll-Like Receptors and p53: Potential Therapeutic Strategies for Infectious Diseases and Cancer.

Fávaro WJ, Nunes OS, Seiva FR, Nunes IS, Woolhiser LK, Durán N, Lenaerts AJ.

Infect Agent Cancer. 2012 Jun 18;7(1):14.

doi: 10.1186/1750-9378-7-14.

2015

Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer.

Garcia PV, Apolinário LM, Böckelmann PK, da Silva Nunes I, Duran N, Fávaro WJ.

Int J Clin Exp Pathol. 2015 May 1;8(5):4427-43.

eCollection 2015.

2016

Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier.

Garcia PV, Seiva FR, Carniato AP, de Mello Júnior W, Duran N, Macedo AM, de Oliveira AG, Romih R, Nunes Ida S, Nunes Oda S, Fávaro WJ.

BMC Cancer. 2016 Jul 7;16:422.

doi: 10.1186/s12885-016-2474-z.

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.

Dias QC, Nunes ID, Garcia PV, Favaro WJ.

Int Braz J Urol. 2016 Sep-Oct;42(5):942-954.

doi: 10.1590/S1677-5538.IBJU.2015.0381.