ABSTRACT: options. Goal for systemic therapy is to

ABSTRACT: 

Pancreatic cancer is a
devastating disease with universally poor prognosis. It is the fourth leading
cause of death in the United States. Survival rate of pancreatic cancer is
<5%. For most of the patients diagnosed at advanced stage surgery is no longer useful because of recurrence and metastasis of the disease. It is considered to be a systemic disease rather than local. For patients with unresectable tumour systemic therapy is the only option. Gemcitabine is the drug of choice for many years but with very poor survival rate. Due to the failure of systemic therapy researchers are focusing on the understanding of molecular pathways involved in this devastating disease. Tumour microenvironment have been studied carefully to design better treatment options. Goal for systemic therapy is to minimize patient's symptoms and prolonging the survival. Genomic analysis of the patients with pancreatic tumour was done in IMPaCT to design personalised treatment for patients. Several clinical trials are now focusing to target the stroma, as it is believed to be a major hurdle in drug delivery and resistance to pancreatic cancer. Stroma also helps the tumour growth. Several genomic alterations have been identified in cancer including TP53 Tumour suppressor gene, K-RAS Oncogene, CDKN2A and SMAD4. 12 processes have been genetically altered in pancreatic cancer.   Introduction:  Pancreatic cancer is a highly toxic disease, that can be systemic or local in nature. It is the 4th common cause of death. Patient diagnose with pancreatic cancer lives up to 12 months even if patient is treated. 5 years survival rate of this deadly disease is just 8%. Failure to survive this cancer is associated with late diagnosis of the disease. Mostly patients are diagnosed when the disease has spread. Only 15%-20% of patients present with resect able tumour while 60%-70% of patients are presented with metastatic disease. The knowledge of pancreatic cancer at molecular level should be understood for designing better treatment options. Patients with pancreatic cancer can be divided in operable and inoperable category. The classic drug of choice for patients in inoperable category is Gemcitabine, and the survival outcome of this just 5 weeks. This poor outcome of chemotherapy is due to multidrug resistant nature of pancreatic cancer cells. Mechanism by which a cancer cell becomes drug resistance is by up regulation of a family of ATP binding cassette (ABC) transporters. This drug efflux pump makes the cancer cells resistant to the chemotherapeutic agents. The initiation of P13K/Akt and Erk/2 pathways is another shared mechanism of obtaining drug resistance. In cancer cells these pathways hinder the initiation of apoptosis. Overexpression of MUC1 in cancer cells shows over stimulation of Erk1/2 and P13k pathways. These studies show likely role of these pathways in conferring drug resistance in MUC1 overexpressing pancreatic cancer cells.   95% of pancreatic cancer occurred due to the in activation of tumour suppressor gen p16/CDKN2AB. During the G1 phase of cell cycle CDK4 phosphorylates and inhibits Rb1 by p16. In this manner p16 is inactivated and G1-CDK increases by phosphorylation of Rb-1, which in turn facilitates progression of cell cycle at G1/S – cell cycle check point. The most commonly inactivated tumour suppressor gen in pancreatic cancer is p53. By deletion in p53 gen, the gen activates the apoptotic pathways. Thus p53 inactivation allows tumour proliferation despite the genetic effect. One of the malignancies which is highly resistant to therapy. One of the challenging solid organ malignancies. Resection of tumour becomes impossible because of the metastasis and the involvement of major vessels with tumour. Pancreatic cancer has become  a challenging disease for Oncology due to its poor survival rates. Recurrence of pancreatic tumour is also common even after complete resection. Studies have shown Gemcitabine based medications is the best option for patients. Only 15% of tumours are resectable at the time of diagnosis. Chemotherapy becomes an option for the non resectable patients. Chemo resistance becomes a clinical problem to treat cancer. K-Ras mutations is higher in pancreatic cancer. These mutations are associated with alcohol intake, cigarette smoking. Alcohol intake of more than 30g can increase the risk of pancreatic cancer. About 10% of the pancreatic cancer has a family history of the disease. History of pancreatitis also increases the risk of pancreatic cancer. Studies have shown reduced risk of pancreatic cancer in patients having hay fever or an animal allergy. The risk is reduced by 20-30%. 30-40% of patients are diagnosed with border line resectable or locally advanced pancreatic cancer but the overall survival of these patients is very poor inspite of distant metastasis for such patient's surgery remains the only cure. Patients can be cured by combining chemotherapy with radiotherapy or surgery. The collection of the population of patients that meet criteria of multimethod approach requires correct identification. The locally advanced pancreatic cancer invades the adjacent structure which makes it more difficult to treat. In contrast the BRPC patients have high incidence of residual microscopic infections. Ro resections are believed to be the only cure of pancreatic cancer. But the resectability criteria for pancreatic cancer is highly controversial. But in chemotherapy clinical trials BRPC patients are least representative population. Clinical Presentation Pancreatic cancer is a silent malignancy. No symptoms occur until the disease is wide spread. Weight loss, pain, anorexia, and sleep problems are usually the first symptoms that may occur. Jaundice, fatigue, depression, stetorrhea, and indigestion can also be the presenting complaints of the patients. Diagnostic Investigation  Multidetector-Row CT For the diagnosis of suspicious pancreatic lesions assessment of vascular, invasion, diagnosis of metastatic lesions and assessment of resectability is now routinely performed by MDCT with contrast medium. In formation of resectability MDCT has an accuracy of 85-95%. Also MDCT has generally 90% of accuracy for diagnosis of pancreatic cancer. Serum Tumour Markers CA19-9 AND CA125 also widely used serum tumour markers for detecting pancreatic tumour, because at 95% specificity, CA19-9 has 68% sensitivity. CA19-9 and CA125 are used in combination as CA125 improves the sensitivity because the concentration of CA125 was raised in 20% of CA19-9 negative cases. PET There have been many limitations of detecting pancreatic cancer using PET because of false positive results. Due to inflammatory masses.   Mata-analysis shows that combination of PET plus CT are highly sensitive to detect pancreatic cancer. MRI Research show that MRI is 83-85% sensitive. And 63% specific. MRI is more preferable than CT because of the precise depiction of lesion without any exposure to radiation. Endoscopic Ultrasonography Endoscopic Ultrasonography is a promising technique to detect lesions of pancreatic cancer. The advantage of using EUS with fine needle aspiration outweighs the use of other diagnostic approaches because in EUS with fine needle aspiration there is a chance of taking the tissue biopsy. The accuracy of this diagnostic test is 85-90% for pancreatic cancer. Progression of Disease Pancreatic cancer is a progressive disease. From normal pancreatic ductal epithelium to infiltrative carcinoma is a slow process. Till the tumour has reached to an unresectable stage patients experience no symptoms, or may be minimal. This stage of pancreatic cancer is called pancreatic intraepithelial neoplasia-3 (PanIN3), at this stage the imaging studies are normal. Next stage the tumour is less than 1cm in size, patient do not experience any symptoms at this stage. Tumour less 2cm in size is the 3rd of pancreatic cancer, and patient do no experience any symptoms unless the tumour is closed to bile duct, resulting in obstructive jaundice. The last stage of pancreatic tumour size is more than 2cm, at this stage only patients have symptoms and the tumour is visible on imaging IMAGING. But only a proportion of tumour is re at this stage. TREATMENT Role of Neo-adjuvant Therapy: To attain better outcomes of the surgery many clinical trials have been set up to investigate the role of new-adjuvant therapy. Patients developing the cancer again do no benefit from surgery only. By giving neo-adjuvant therapy has a better effect in tumour pre operatively rather than post operatively, because the resected tumour bed has poor drug delivery due to hypoxia. Another important benefit of neo-adjuvant therapy is the tumour margin can possibly be at Ro resection and this improve the survival outcomes of the patients. How ever the role of neo-adjuvant therapy is not well supported by the clinical trials in the past. A study was carried that the University of Texas that suggested that by administration of neo-adjuvant therapy the role of positive margins R1 are decreased. This study was a single centre study and hence does not supports the idea of neo-adjuvant therapy due to limitation.   Surgery: Surgery is the only curative treatment for pancreatic cancer and the only method to improve the survival rates of the patients. Resectability of the tumour involves surgical expertise. A borderline resectable tumour is defined when no metastasis is present and the superior mesenteric vein or portal vein is the only venous involvement and gastroduodenal artery encasement is up to hepatic artery and the tumour support of superior mesenteric artery is less than equal to 180°.   Chemotherapy: Chemotherapy is vital for metastatic pancreatic cancer. Many clinical trials were performed to support the efficacy of Gemcitabine.  A clinical trial on 126 patients was done. 63 patients received Gemcitabine 1000mg/ once a week for continuously 7 weeks, followed by one week of no medication then once a week for 3 weeks consecutive out of every four weeks and 63 patients were treated with Fluorouracil (5 FU) 600mg/m2 once a week. This study shows that Gemcitabine is more effective than 5 FU. One year survival rate of Gemcitabine was 18% and for 5 FU was only 2%. Since then Gemcitabine is the drug of choice for pancreatic cancer. In another randomised clinical trial Erlotinib (HER1/EGFR tyrosine kinase inhibitor was added to Gemcitabine that showed promising result. Human epidermal growth factor receptor type 1 (HER1/EGFR) is overexpressed in pancreatic tumours.   A multicentre randomised trial called ACCORD-1 was conducted and 342 patients were enrolled in the study, patients were divided 171 in each group. Gemcitabine was tested against Folfirinox. Gemcitabine was administered at the dose of 1000mg/m2 i.v. infusion for 7 weeks, following a rest of one week. Folfirinox regimen contained Oxaliplatin 85mg/m2 (a platinum based antineoplastic agent), Leucovorin 400mg/m2 (folinic acid- a vitamin B derivative). Irinotecan 180mg/m2 (a topoisomerase inhibitor) followed by bolus Fluorouracil 400mg/m2 + infusional Fluorouracil 240mg/m2. Folfirinox showed better results than Gemcitabine. Overall survival of patients receiving Folfirinox was increased by four months than Gemcitabine. However patients selection was very crucial in this study as Folfirinox was potentially toxic combination of drugs and had many side effects.   In 2013 Nab-Paclitaxel was combined with Gemcitabine and Gemcitabine alone was tested in a clinical trial that included 861 patients. 430 patients were given Nab-Paclitaxel 125mg/m2 followed by 1000mg/m2 on 1, 8 and 15th day every 4 weeks. Gemcitabine alone was given 1000mg/m2 weekly for 7-8 weeks. Combination of Nab-Paclitaxel plus Gemcitabine significantly improved the survival with 85 months. Nab-Paclitaxel was believed to improved the intra tumoral concentration of Gemcitabine.   Capecitabine combined with Oxaliplatin (Capox) was tested on patients. This was compared to Capecitabine plus Gemcitabine and Oxaliplatin with Gemcitabine. All these three combination of drugs was tested on 190 patients. Results demonstrated that these chemotherapy doublets had same efficacy. Each chemotherapy doublet had different side effects and toxicity but all these effects were manageable.   Advances in Managing Metastatic Pancreatic cancer: Gemcitabine has been a choice of drug for metastatic disease. But chemotherapy doublets including Gemcitabine failed to provide improvement in survival. EGFR tyrosine kinase inhibitor Erlotinib combined with Gemcitabine showed improved survival but this study was irrelevant to most of the patients due to the lack of biomarkers in response. Further research might be needed to identify patients that can benefit from EGFR inhibitors.   As pancreatic cancer is activated because of the mutations in KRAS oncogene. In this regard a K-Ras mutated wild type mouse model was designed. In normal mouse metaplasia was largely dependent on activation of EGFR. Ras pathway is responsible for EGFR signalling. But by inhibiting EGFR expression over ruled the development of pancreatic ductal adenocarcinoma. In the same study when EGFR was down regulated in TP53 wild type mouse model tumour development was not inhibited.   Novel Treatment Opportunities in Pancreatic Cancer: Target of Stromal Compartment: As one of the important characteristics of pancreatic cancer is dense desmoplastic reaction. The composition of this desmoplasia (stroma) is Extracellular Matrix (ECM) proteins, endothelial cells, fibroblasts, immune cells and neurons. Research shows pancreatic cells release a variety of factors that activate stroma. In turn stromal cells releases substances that stimulate tumour growth and become resistant to chemotherapy. As the understanding of tumour biology is increasing there are new therapies in development to target the stroma. From this understanding therapies are more directed towards the stromal physiology. A mouse model was used in this study an anti fibrotic drug was used to inhibit the production of TGF-b, PDGF and Collagen Type 1, used in the treatment of pulmonary fibrosis. Studies have shown that treatment with Nab-Paclitaxel depletes the stroma through SPARC inhibition and inhibits tumour growth as well.             Recent research shows that activated pancreatic stellate cells (PSCs) are crucial in the generation of desmoplastic stroma and also affects the biology of the pancreatic cancer cells. PSC act in dose-dependant manner and increase pancreatic cancer cell proliferation, migration, invasion and colony formation of the cells. This research proves that stromal cells release factors that increase the tumour growth and impair the response of chemo and radio therapies. Drug Delivery: Barrier in drug delivery due to high intestitial fluid pressure is a major problem in solid organ tumours. Resistance to drugs in pancreatic cancer is due to the vascular collapse and hypo perfusions. Diffusion is highly dependant on concentration gradients, this is determined by hydrostatic pressure gradient by which fluid efflux is promoted from vessels in the opposite way of fluid retention. In normal organs interstitial fluid pressures (IFPs) are relatively low. But in tumours high IFP are responsible to compromise the drug delivery which is administered systemically. As pancreatic cancer consists of a dense extracellular matrix and high concentration on interstitial hyaluronan (HA) and a compact vasculature. As research shows that this vasculature lacks fenestrae. This interstitial fluid is HA dependent (gel like) less mobile fluid same as fluid in the joint spaces. The chemo-resistance nature of pancreatic cancer may be the result of ATP-dependent membrane bound drug efflux pump-MDR1. P-Glycoprotein and MRP1. A research was done to evaluate the expression of MDR1Pgp and MRP-1 in pancreatic cancer. This study group had 45 patients of pancreatic cancer and immunohistochemistry assays was done using anti MDR1 and anti MRP1 monoclonal antibodies. 93.3% of the pancreatic cancer samples were MDR1 P-gp and 31% were MRP1 specific. This study indicated the expression of drug efflux pump (MDR1 P-gp) is common in pancreatic tumour and inhibition of MDR1 P-gp expression can help in the reversal of chemo resistance. Overcoming Drug Resistance Overexpression of drug efflux pumps are responsible to decreased accumulation of drug in the cell. ATP binding cassette (ABC) transporters expel the non polar compound from plasma membrane utilising the energy from ATP hydrolysis. 49 human ABC transporters have been recognised till date. Epithelial mesenchymal transition (EMT) has been implicated as yet another potential mechanisms for drug resistance. Mesenchymal phenotype pancreatic cancers are Gemcitabine resistant. Research shows defects signalling pathways TGF-B, Wnt, Hedgehog, Notch and NF-KB are crucial for induction of EMT. Hedgehog (HH) pathway is one of the core signalling pathways in pancreatic cancer. Activation of hedgehog (HH) signalling occurs in stroma, inhibiting smoothened SMO inhibitors result in inhibited tumour growth in mice. In KPC mouse model, the combination of gemcitabine and SMO inhibitor (IPI-926) enhanced drug delivery and improved the survival as well. But this study could not be translated into clinic. Inhibition of hedgehog signalling pathway results in angiogenesis and impairs the drug delivery in mouse model R63.   Cancer Stem Cells  Recurrence of tumour after resection is yet another hurdle in the treatment of pancreatic cancer this due to the presence of pancreatic cancer stem cells. Cancer stem cells are identified by the expression of self surface markers CD44+, CD24+ and epithelial specific antigen (ESA)+ . Cells expressing these cell surface markers have the potential to self renewal, highly tumorigenic and resemble the patient primary tumour. CD1 33 has recently been identified as another cell surface marker of pancreatic cancer. Recent studies also suggest Aldehyde Dehydrogenase (ALDH) activity is yet another marker for pancreatic cancer stem cell. CD24, CD44, & ESA stem cell markers are potentially gemcitabine resistant in pancreatic cancer. These resistance cancer stem cells have properties of EMT. Treatment with ionizing radiation and gemcitabine results in the cell population CD44+, CD24+, ESA+ cell markers in primary pancreatic cancer xenografts.     Cell proliferation, invasion, angiogenesis, metastasis and drug resistance is induced in pancreatic cancer by activation of NFKB. Inhibiting the NFKB pathway can open the doors to cancer treatment. In a recent research on orthotopic animal model it its evident that 3, 3-diindollymethane (DIM) a plant derived product inhibit cell growth and apoptosis by inhibiting in NF-KB.  Mutations in key genes may result in drug resistance in many types of cancers. Cells that are BRCA1 and BRCA2 deficient are affected by DNA cross linking agents. Carboplatin (A platinum based anti neo plastic drug) can mutate BRCA1 and BRCA2 genes. Both of these genes are very important in cancer and combination of deficiencies in the expression lead to cell death. This targeting of one gene in cancer which become lethal to tumour cell but less toxic to the normal cell.     MRP1, MRP3, MRP4, MRP5 and P-Glycoprotein are well known drug resistant protein. These proteins are highly expressed in pancreatic cells. Reversin 121 (R121) can sensitise cell to chemotherapy drugs. R121 binds to MDR proteins and inhibit substrate  extrusion. Research shows that in vivo treatment using chemotherapy drugs 5-FU, gemcitabine, cisplatin in combination with R121 reduced peritoneal, hepatic and pulmonary metastasis compared with single chemotherapeutic agent. 47 patients were enrolled in a randomised trial, 23 patients were treated with low dose cisplatin (30mg/m2), 5-FU, Interferon alpha and external beam radiation.   Inhibition of NF-KB pathway by using specific inhibitors and others molecular therapies. Many agents like curcumin, resveratrol, green tea, polyphenols, silymarin and caffic acid phenethyl ester have shown activity of inhibition of NF-KB. By using siRNA specifically targeting NF-KB can improve Gemcitabine response. Another benefit of blocking NF-KB pathway is the decrease of drug resistance, but targeting or inhibiting one pathway may not be enough for pancreatic cancer treatment. Multiple therapies targeting multiple pathway may improve the treatment strategies of pancreatic cancer. Research shows that               3,3-diindoyle- methane (DIM) can kill pancreatic cancer cells in vivo. Using an orthotopic animal model, use of DIM + Oxaliplatin reduced the tumour size.   National and international projects are using the technique of next generation sequencing (NGS) for studying cancer genomics. NGS can be used to identify genomic targets and can analyse sensitivity to given therapies. But translation of NGS in clinic has many limitations like cost, choice of assay, tissue collection and even time of tissue collection. Yet NGS open the doors to biomarker defined trials, these trials will help in linking tumour genomics to therapeutic efficacy. In future a more understanding of genomic sequencing will be available.   Correlation of Genetic Alterations: Correlation of genetic alterations with pattern of disease and responses to different chemotherapeutic agents can help translating these findings into clinic. In the individualised Molecular Pancreatic Cancer Therapy (IMPaCT) trial tumour biopsies were collected from 93 patients, 76 patients were screened. 14 were K-RAS wild type that were treated with Gemcitabine + Erlotinib, 5 were HER2-positive sub group that were treated with Gemcitabine+ Trastuzumab and 2 cases were mutation in BRCA2 that were treated with 5 FU + Mytomycin C. This study provided the idea that screening tumour biopsies to identify molecular targets is possible in real time but this needs to be further investigative. Mesenchymal Stem Cells in Pancreatic Cancer Mesenchymal stem cells have recently been identified in tumours. As cell based therapy is now emerging for treatment of solid tumours MSCs are helpful in target moieties because of the presence of migratory ability. A study showed that 50% of the tumour growth was inhibited by IV injection of MSC's expressing CCL5. Promoter driven herpes simplex virus, thymidine, kinase (HSV-TK) gene and even reduced liver metastasis. A recent research shows that tumour can be targeted for better drug delivery using multi spectral opto-acoustic tomography (MSOT and thernostic nanoparticles and fluorescent dyes. Colloidle mesoporous silica nanoparticles (CMS) were synthesis conjugative with V7 peptide. These particles were analysed by using transmission electron microscopy and accumulation of these particles were observed. These nanoparticles can be used to identify pancreatic tumour with high sensitivity and specificity for targeted drug delivery. 

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