10/08/2017

Animal models of cancer -pancreatic cancer

P-MAPA immunotherapy in the treatment of pancreatic cancer

Overview

Pancreatic cancer (PC) is a highly aggressive and lethal cancer characterized by invasiveness, local and extensive dissemination at time of diagnosis and resistance to treatment.

The management modalities of pancreatic cancer may include surgical resection, chemotherapy, radiotherapy, and chemoradiation. Due to rapid cancer cell proliferation, aggressive local invasion, metastasis, high rate of local recurrence, and resistance to most forms of treatment, pancreatic cancer remains highly lethal even when surgically resected.

The median survival for locally advanced pancreatic cancer is only between 9 and 15 months, according to The American Cancer Society. Only 18% of the patients with advanced pancreatic ductal adenocarcinoma remain alive at 1 year, and 4% at 5 years (Hidalgo M et al., 2015).

The prognostic is dismal for metastatic disease. Studies report median survival ranges for patients presenting metastatic disease between 2.8 and 5.7 months (Carrato A et al., 2015).

Current Treatment Options

Gemcitabine therapy has been the standard first-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer, but the treatment has only marginally improved the median survival rate.

Various gemcitabine-based schemes have been attempted to improve the clinical results. One of them, Gemcitabine plus Cisplatin (GemCis), has showed synergistic effects; high toxicity rates, however, were observed (Ouyang G et al, 2016).

 

FOLFIRINOX (FFX) - a combination of fluorouracil [5-FU], leucovorin, irinotecan and oxaliplatin - was introduced into clinical practice in 2010 in the treatment of metastatic PC and is associated with better survival time (W Marsh R De Wet al., 2015, Conroy T et al., 2011).

Meantime, FFX regime and/or FFX-type combinations can be highly toxic and their side effects can be more intense than the standard therapy (gemcitabine) monotherapy.

Despite advances, the median survival time of advanced and /or metastatic PC patients remains between 4 and 11 months (Von Hoff D et al., 2013). Therefore, new treatment options are urgently needed to improve the survival rates of patients with PC.

As dysregulation of the immune system facilitates PC development, immunotherapy alone or associated with chemotherapy may be a valuable therapeutic strategy for the treatment of PC (Paniccia A et al., 2015).

In this setting, promising new approaches are emerging. The strategies described by Ghansah and Chang - Gemcitabine chemotherapy associated respectively with a dendritic cell vaccine and a TLR2 agonist - lead to a significant decrease of pancreatic tumor in animal model (Ghansah T et al., 2013, Chang LS et al., 2016). 

Clinical trials have also showed positive results of chemotherapeutic agents associated with immunomodulator ones (Hirooka Y et al., 2009, Kimura Y et al., 2012). After evaluating 18 studies, from which 14 on immunotherapy associated with chemotherapy and 4 on immunotherapy alone, Zhang concluded that the drug association is more effective than immunotherapy alone (Zhang B et al., 2016). Kimura also concluded that Gemcitabine chemotherapy can have good therapeutic responses when associated with immunotherapy (Kimura Y et al., 2012). 

Toll-like receptors (TLRs), mainly TLR4, may be important role in the treatment of PC. TLR4 signaling pathway promotes cytokines production, such as interferons, which are powerful inducers of tumor cell death (Zhang JJ et al., 2010). Specifically, IFN-γ stimulates immune cells, blocks tumor growth and detects metastasis. TLR4 signaling pathway is dependent on Myd88, which induces IFN-γ production (Beatty GL et al., 2001, Sun D et al. 2006).

In this setting P-MAPA immunotherapy may be a valuable option for treatmemt of pancreatic cancer.

In fact, preclinical studies carried out in several animal models have indicated that P-MAPA modulates the innate and adaptive immune systems, increases IL-2 and IFN-γ levels and decreases IL-10 levels, reversing the tumor-induced immunosuppression and blocking the tumor progression. The result is the host protection and high survival rates of the animals.

Taking together, the data pave the way and provides the scientific rationale for the use of P-MAPA immunotherapy alone and in association with chemotherapy in the treatment of PC.

Therefore, to explore the possibilities of the use of P-MAPA immunotherapy in the treatment  of pancreatic cancer,  a experiment using Fischer 344 male rats presenting PC chemically induced by DMBA  was performed

Gemcitabine, was used as positive control and in association with P-MAPA.

Experimental aims

1) to explore and compare the effects of P-MAPA monotherapy and associated with Gemcitabine in the treatment of chemically induced PC;

2) to verify if P-MAPA monotherapy or associated with Gemcitabine would be able to induce effects on cytokines associated with a Th-1 type response;

3) to verify if P-MAPA immunotherapy associated with Gemcitabine would present signs of additional toxicity.

Experimental Design

PC was induced in 40 rats ( male Fischer 344) using 200 µg of 7, 12-Dimethylbenz (a) anthracene (DMBA) in the pancreas head. Other 10 rats (not induced) composed the Control Group. After 120 days of induction, all animals were subdivided into five groups (10 animals per group): Group 1: Control Group; Group 2: DMBA Group; Group 3: P-MAPA; Group 4: Gemcitabine Group; Group 5: P-MAPA + Gemcitabine Group.

Control group (1): animals received intraperitoneal applications of 5 mL/kg 0.9% physiological solution, three times per week for six weeks; DMBA (cancer) group (2): animals received the same treatment of the control group; P-MAPA group (3): animals received intraperitoneal applications of 5 mg/kg P-MAPA (Farmabrasilis, São Paulo, Brazil), three times per week for six weeks; DMBA + Gemcitabine group (4): animals received intraperitoneal applications of 10 mg/kg Gemcitabine once a week for six weeks; P-MAPA + Gemcitabine group (5): animals received intraperitoneal applications of 5 mg/kg P-MAPA three times by week for three weeks followed by intraperitoneal application of 10 mg/kg Gemcitabine once a week for the following three weeks.

Results

P-MAPA immunotherapy alone and in association with Gemcitabine showed impressive results in the treatment of PC in animal model:

P-MAPA-treated animals presented 40% of histopathological recovery, expanded to 80% in P-MAPA plus Gemcitabine-treated animals. 

The complete experimental data and the scientific rationale  for the use of P-MAPA immnotherapy in the treatment of pancreatic cancer, may be acessed by the link below (PDF files):

Scientific rationale for the use of P-MAPA immunotherapy in the treatment of pancreatic cancer