ABSTRACT: options. Goal for systemic therapy is to

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Last updated: September 28, 2019

ABSTRACT:  Pancreatic cancer is adevastating disease with universally poor prognosis. It is the fourth leadingcause of death in the United States. Survival rate of pancreatic cancer is<5%. For most of the patients diagnosed at advanced stage surgery is nolonger useful because of recurrence and metastasis of the disease. It isconsidered to be a systemic disease rather than local.

For patients withunresectable tumour systemic therapy is the only option. Gemcitabine is thedrug of choice for many years but with very poor survival rate. Due to thefailure of systemic therapy researchers are focusing on the understanding ofmolecular pathways involved in this devastating disease.

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Tumourmicroenvironment have been studied carefully to design better treatmentoptions. Goal for systemic therapy is to minimize patient’s symptoms andprolonging the survival. Genomic analysis of the patients with pancreatictumour was done in IMPaCT to design personalised treatment for patients.Several clinical trials are now focusing to target the stroma, as it isbelieved to be a major hurdle in drug delivery and resistance to pancreaticcancer.

Stroma also helps the tumour growth. Several genomic alterations havebeen identified in cancer including TP53 Tumour suppressor gene, K-RAS Oncogene,CDKN2A and SMAD4. 12 processes have been genetically altered in pancreaticcancer.

 Introduction: Pancreatic cancer is a highly toxic disease,that can be systemic or local in nature. It is the 4th common causeof death. Patient diagnose with pancreatic cancer lives up to 12 months even ifpatient 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% ofpatients present with resect able tumour while 60%-70% of patients arepresented with metastatic disease. The knowledge of pancreatic cancer atmolecular level should be understood for designing better treatment options.Patients with pancreatic cancer can be divided in operable and inoperablecategory. The classic drug of choice for patients in inoperable category isGemcitabine, and the survival outcome of this just 5 weeks. This poor outcomeof chemotherapy is due to multidrug resistant nature of pancreatic cancercells.

Mechanism by which a cancercell becomes drug resistance is by up regulation of a family of ATP bindingcassette (ABC) transporters. This drug efflux pump makes the cancer cellsresistant to the chemotherapeutic agents.The initiation of P13K/Akt andErk/2 pathways is another shared mechanism of obtaining drug resistance.

Incancer cells these pathways hinder the initiation of apoptosis. Overexpressionof MUC1 in cancer cells shows over stimulation of Erk1/2 and P13k pathways. These studies show likely roleof these pathways in conferring drug resistance in MUC1 overexpressingpancreatic cancer cells.

 95% of pancreatic canceroccurred due to the in activation of tumour suppressor gen p16/CDKN2AB. Duringthe G1 phase of cell cycle CDK4 phosphorylates and inhibits Rb1 by p16. In thismanner 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 checkpoint. The most commonly inactivated tumour suppressor gen in pancreatic canceris p53.

By deletion in p53 gen, the gen activates the apoptotic pathways. Thusp53 inactivation allows tumour proliferation despite the genetic effect. One of the malignancies whichis highly resistant to therapy. One of the challenging solid organmalignancies. Resection of tumour becomesimpossible because of the metastasis and the involvement of major vessels withtumour. Pancreatic cancer has become  achallenging disease for Oncology due to its poor survival rates. Recurrence ofpancreatic tumour is also common even after complete resection.

Studies haveshown Gemcitabine based medications is the best option for patients. Only 15%of tumours are resectable at the time of diagnosis. Chemotherapy becomes anoption for the non resectable patients. Chemo resistance becomes a clinicalproblem to treat cancer. K-Ras mutations is higher inpancreatic cancer. These mutations are associated with alcohol intake,cigarette smoking. Alcohol intake of more than 30g can increase the risk ofpancreatic cancer. About 10% of the pancreatic cancer has a family history of thedisease.

History of pancreatitis also increases the risk of pancreatic cancer. Studies have shown reducedrisk of pancreatic cancer in patients having hay fever or an animal allergy.The risk is reduced by 20-30%.

30-40% of patients arediagnosed with border line resectable or locally advanced pancreatic cancer butthe overall survival of these patients is very poor inspite of distantmetastasis for such patient’s surgery remains the only cure. Patients can be cured bycombining chemotherapy with radiotherapy or surgery. The collection of thepopulation of patients that meet criteria of multimethod approach requirescorrect identification. The locally advanced pancreatic cancer invades theadjacent structure which makes it more difficult to treat. In contrast the BRPCpatients have high incidence of residual microscopic infections. Ro resectionsare believed to be the only cure of pancreatic cancer. But the resectabilitycriteria for pancreatic cancer is highly controversial.

But in chemotherapyclinical trials BRPC patients are least representative population.Clinical PresentationPancreatic cancer is a silentmalignancy. No symptoms occur until the disease is wide spread.

Weight loss,pain, anorexia, and sleep problems are usually the first symptoms that mayoccur. Jaundice, fatigue, depression, stetorrhea, and indigestion can also bethe presenting complaints of the patients. Diagnostic Investigation Multidetector-Row CTFor the diagnosis ofsuspicious pancreatic lesions assessment of vascular, invasion, diagnosis ofmetastatic lesions and assessment of resectability is now routinely performedby MDCT with contrast medium. In formation of resectabilityMDCT has an accuracy of 85-95%. Also MDCT has generally 90% of accuracy fordiagnosis of pancreatic cancer.Serum Tumour MarkersCA19-9 AND CA125 also widelyused serum tumour markers for detecting pancreatic tumour, because at 95%specificity, CA19-9 has 68% sensitivity.CA19-9 and CA125 are used incombination as CA125 improves the sensitivity because the concentration ofCA125 was raised in 20% of CA19-9 negative cases.PET There have been manylimitations of detecting pancreatic cancer using PET because of false positiveresults.

Due to inflammatory masses.  Mata-analysis shows that combinationof PET plus CT are highly sensitive to detect pancreatic cancer.MRIResearch show that MRI is83-85% sensitive. And 63% specific. MRI is more preferable than CTbecause of the precise depiction of lesion without any exposure to radiation. Endoscopic Ultrasonography Endoscopic Ultrasonography isa promising technique to detect lesions of pancreatic cancer.

The advantage ofusing EUS with fine needle aspiration outweighs the use of other diagnosticapproaches because in EUS with fine needle aspiration there is a chance oftaking the tissue biopsy. The accuracy of this diagnostic test is 85-90% forpancreatic cancer. Progression of Disease Pancreatic cancer is aprogressive disease.

From normal pancreatic ductal epithelium to infiltrativecarcinoma is a slow process. Till the tumour has reached to an unresectablestage patients experience no symptoms, or may be minimal. This stage ofpancreatic cancer is called pancreatic intraepithelial neoplasia-3 (PanIN3), atthis stage the imaging studies are normal. Next stage the tumour is less than1cm in size, patient do not experience any symptoms at this stage. Tumour less2cm in size is the 3rd of pancreatic cancer, and patient do noexperience any symptoms unless the tumour is closed to bile duct, resulting inobstructive jaundice. The last stage of pancreatic tumour size is more than2cm, at this stage only patients have symptoms and the tumour is visible onimaging IMAGING. But only a proportion of tumour is re at this stage.

TREATMENT Role of Neo-adjuvant Therapy:To attain better outcomes ofthe surgery many clinical trials have been set up to investigate the role ofnew-adjuvant therapy. Patients developing the cancer again do no benefit fromsurgery only. By giving neo-adjuvant therapy has a better effect in tumour preoperatively rather than post operatively, because the resected tumour bed haspoor drug delivery due to hypoxia.Another important benefit ofneo-adjuvant therapy is the tumour margin can possibly be at Ro resection andthis improve the survival outcomes of the patients. How ever the role ofneo-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 byadministration of neo-adjuvant therapy the role of positive margins R1 aredecreased.

This study was a single centre study and hence does not supports theidea of neo-adjuvant therapy due to limitation.  Surgery:Surgery is the only curativetreatment for pancreatic cancer and the only method to improve the survivalrates of the patients. Resectability of the tumour involves surgical expertise.A borderline resectable tumour is defined when no metastasis is present and thesuperior mesenteric vein or portal vein is the only venous involvement andgastroduodenal artery encasement is up to hepatic artery and the tumour supportof superior mesenteric artery is less than equal to 180°. Chemotherapy: Chemotherapy is vital formetastatic pancreatic cancer.

Many clinical trials were performed to supportthe efficacy of Gemcitabine.  A clinicaltrial on 126 patients was done. 63 patients received Gemcitabine 1000mg/ once a week for continuously 7 weeks, followedby one week of no medication then once a week for 3 weeks consecutive out ofevery four weeks and 63 patients were treated with Fluorouracil (5 FU) 600mg/m2once a week. This study shows that Gemcitabine is more effective than 5 FU.

Oneyear survival rate of Gemcitabine was 18% and for 5 FU was only 2%. Since thenGemcitabine is the drug of choice for pancreatic cancer.In another randomised clinical trialErlotinib (HER1/EGFR tyrosine kinase inhibitor was added to Gemcitabine thatshowed promising result. Human epidermal growth factor receptor type 1 (HER1/EGFR)is overexpressed in pancreatic tumours. A multicentre randomised trial calledACCORD-1 was conducted and 342 patients were enrolled in the study, patientswere divided 171 in each group. Gemcitabine was tested against Folfirinox.

Gemcitabine was administered at the dose of 1000mg/m2 i.v. infusion for 7weeks, following a rest of one week. Folfirinox regimen contained Oxaliplatin85mg/m2 (a platinum based antineoplastic agent), Leucovorin 400mg/m2 (folinicacid- 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 patientsreceiving Folfirinox was increased by four months than Gemcitabine.

Howeverpatients selection was very crucial in this study as Folfirinox was potentiallytoxic combination of drugs and had many side effects. In 2013 Nab-Paclitaxel was combined withGemcitabine and Gemcitabine alone was tested in a clinical trial that included861 patients. 430 patients were given Nab-Paclitaxel 125mg/m2 followed by1000mg/m2 on 1, 8 and 15th day every 4 weeks. Gemcitabine alone wasgiven 1000mg/m2 weekly for 7-8 weeks. Combination of Nab-Paclitaxel plusGemcitabine significantly improved the survival with 85 months.

Nab-Paclitaxelwas believed to improved the intra tumoral concentration of Gemcitabine. Capecitabine combined with Oxaliplatin(Capox) was tested on patients. This was compared to Capecitabine plusGemcitabine and Oxaliplatin with Gemcitabine.

All these three combination ofdrugs was tested on 190 patients. Results demonstrated that these chemotherapydoublets had same efficacy. Each chemotherapy doublet had different sideeffects and toxicity but all these effects were manageable.

 Advancesin Managing Metastatic Pancreatic cancer:Gemcitabine has been a choice of drugfor metastatic disease. But chemotherapy doublets including Gemcitabine failed toprovide improvement in survival. EGFR tyrosine kinase inhibitor Erlotinibcombined with Gemcitabine showed improved survival but this study wasirrelevant to most of the patients due to the lack of biomarkers in response.

Further research might be needed to identify patients that can benefit fromEGFR inhibitors. As pancreatic cancer is activatedbecause of the mutations in KRAS oncogene. In this regard a K-Ras mutated wildtype mouse model was designed. In normal mouse metaplasia was largely dependenton activation of EGFR. Ras pathway is responsible for EGFR signalling. But byinhibiting EGFR expression over ruled the development of pancreatic ductaladenocarcinoma. In the same study when EGFR was down regulated in TP53 wildtype mouse model tumour development was not inhibited. NovelTreatment Opportunities in Pancreatic Cancer:Targetof Stromal Compartment:As one of the important characteristicsof pancreatic cancer is dense desmoplastic reaction.

The composition of thisdesmoplasia (stroma) is Extracellular Matrix (ECM) proteins, endothelial cells,fibroblasts, immune cells and neurons. Research shows pancreatic cells releasea variety of factors that activate stroma. In turn stromal cells releasessubstances that stimulate tumour growth and become resistant to chemotherapy.As the understanding of tumour biology is increasing there are new therapies indevelopment to target the stroma.

From this understanding therapies are moredirected towards the stromal physiology. A mouse model was used in this studyan anti fibrotic drug was used to inhibit the production of TGF-b, PDGF andCollagen Type 1, used in the treatment of pulmonary fibrosis. Studies haveshown that treatment with Nab-Paclitaxel depletes the stroma through SPARCinhibition and inhibits tumour growth as well.            Recentresearch shows that activated pancreatic stellate cells (PSCs) are crucial inthe generation of desmoplastic stroma and also affects the biology of thepancreatic cancer cells. PSC act in dose-dependant manner and increasepancreatic cancer cell proliferation, migration, invasion and colony formationof the cells. This research proves that stromal cells release factors thatincrease the tumour growth and impair the response of chemo and radiotherapies.DrugDelivery:Barrier in drug delivery due to highintestitial fluid pressure is a major problem in solid organ tumours.

Resistance to drugs in pancreatic cancer is due to the vascular collapse andhypo perfusions. Diffusion is highly dependant on concentration gradients, thisis determined by hydrostatic pressure gradient by which fluid efflux ispromoted from vessels in the opposite way of fluid retention. In normal organsinterstitial fluid pressures (IFPs) are relatively low. But in tumours high IFPare responsible to compromise the drug delivery which is administeredsystemically. As pancreatic cancer consists of a dense extracellular matrix andhigh concentration on interstitial hyaluronan (HA) and a compact vasculature.As research shows that this vasculature lacks fenestrae. This interstitialfluid is HA dependent (gel like) less mobile fluid same as fluid in the jointspaces. The chemo-resistance nature ofpancreatic cancer may be the result of ATP-dependent membrane bound drug effluxpump-MDR1.

P-Glycoprotein and MRP1. A research was done to evaluate the expressionof MDR1Pgp and MRP-1 in pancreatic cancer. This study group had 45 patients ofpancreatic cancer and immunohistochemistry assays was done using anti MDR1 andanti MRP1 monoclonal antibodies. 93.3% of the pancreatic cancer samples wereMDR1 P-gp and 31% were MRP1 specific.

This study indicated the expression ofdrug efflux pump (MDR1 P-gp) is common in pancreatic tumour and inhibition ofMDR1 P-gp expression can help in the reversal of chemo resistance. OvercomingDrug Resistance Overexpression of drug efflux pumps areresponsible to decreased accumulation of drug in the cell. ATP binding cassette(ABC) transporters expel the non polar compound from plasma membrane utilisingthe energy from ATP hydrolysis. 49 human ABC transporters have been recognisedtill date. Epithelial mesenchymal transition (EMT)has been implicated as yet another potential mechanisms for drug resistance.Mesenchymal phenotype pancreatic cancers are Gemcitabine resistant. Researchshows defects signalling pathways TGF-B, Wnt, Hedgehog, Notch and NF-KB arecrucial for induction of EMT. Hedgehog (HH) pathway is one of the coresignalling pathways in pancreatic cancer.

Activation of hedgehog (HH)signalling occurs in stroma, inhibiting smoothened SMO inhibitors result ininhibited tumour growth in mice. In KPC mouse model, the combination ofgemcitabine and SMO inhibitor (IPI-926) enhanced drug delivery and improved thesurvival as well. But this study could not be translated into clinic. Inhibition of hedgehog signallingpathway results in angiogenesis and impairs the drug delivery in mouse modelR63.  CancerStem Cells Recurrence of tumour after resection is yetanother hurdle in the treatment of pancreatic cancer this due to the presenceof pancreatic cancer stem cells. Cancer stem cells are identified by theexpression of self surface markers CD44+, CD24+ and epithelial specific antigen(ESA)+ .

Cells expressing these cell surface markers have the potential to selfrenewal, highly tumorigenic and resemble the patient primary tumour. CD1 33 hasrecently been identified as another cell surface marker of pancreatic cancer.Recent studies also suggest Aldehyde Dehydrogenase (ALDH) activity is yetanother marker for pancreatic cancer stem cell. CD24, CD44, & ESA stem cellmarkers are potentially gemcitabine resistant in pancreatic cancer. Theseresistance cancer stem cells have properties of EMT. Treatment with ionizingradiation 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 byactivation of NFKB.

Inhibiting the NFKB pathway can open the doors to cancertreatment. In a recent research on orthotopic animal model it its evident that3, 3-diindollymethane (DIM) a plant derived product inhibit cell growth andapoptosis by inhibiting in NF-KB.  Mutations in key genes may result indrug resistance in many types of cancers. Cells that are BRCA1 and BRCA2 deficientare affected by DNA cross linking agents.

Carboplatin (A platinum based antineo plastic drug) can mutate BRCA1 and BRCA2 genes. Both of these genes arevery important in cancer and combination of deficiencies in the expression leadto cell death. This targeting of one gene in cancer which become lethal totumour cell but less toxic to the normal cell.   MRP1, MRP3, MRP4, MRP5 andP-Glycoprotein are well known drug resistant protein. These proteins are highlyexpressed in pancreatic cells.

Reversin 121 (R121) can sensitise cell tochemotherapy drugs. R121 binds to MDR proteins and inhibit substrate  extrusion. Research shows that in vivotreatment using chemotherapy drugs 5-FU, gemcitabine, cisplatin in combinationwith R121 reduced peritoneal, hepatic and pulmonary metastasis compared withsingle chemotherapeutic agent. 47 patients were enrolled in arandomised 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 usingspecific inhibitors and others molecular therapies. Many agents like curcumin,resveratrol, green tea, polyphenols, silymarin and caffic acid phenethyl esterhave shown activity of inhibition of NF-KB. By using siRNA specifically targetingNF-KB can improve Gemcitabine response.

Another benefit of blocking NF-KBpathway is the decrease of drug resistance, but targeting or inhibiting onepathway may not be enough for pancreatic cancer treatment. Multiple therapiestargeting multiple pathway may improve the treatment strategies of pancreaticcancer. Research shows that               3,3-diindoyle- methane (DIM) cankill pancreatic cancer cells in vivo. Using an orthotopic animal model, use ofDIM + Oxaliplatin reduced the tumour size.  National and international projects areusing the technique of next generation sequencing (NGS) for studying cancergenomics.

NGS can be used to identify genomic targets and can analysesensitivity to given therapies. But translation of NGS in clinic has manylimitations like cost, choice of assay, tissue collection and even time oftissue collection.Yet NGS open the doors to biomarkerdefined trials, these trials will help in linking tumour genomics totherapeutic efficacy. In future a more understanding of genomic sequencing willbe available. Correlationof Genetic Alterations: Correlationof genetic alterations with pattern of disease and responses todifferent chemotherapeutic agents can help translating these findings intoclinic. In the individualised Molecular Pancreatic Cancer Therapy (IMPaCT)trial tumour biopsies were collected from 93 patients, 76 patients werescreened. 14 were K-RAS wild type that were treated with Gemcitabine +Erlotinib, 5 were HER2-positive sub group that were treated with Gemcitabine+ Trastuzumaband 2 cases were mutation in BRCA2 that were treated with 5 FU + Mytomycin C.This study provided the idea that screening tumour biopsies to identifymolecular targets is possible in real time but this needs to be furtherinvestigative.

MesenchymalStem Cells in Pancreatic CancerMesenchymal stem cells have recentlybeen identified in tumours. As cell based therapy is now emerging for treatmentof solid tumours MSCs are helpful in target moieties because of the presence ofmigratory ability. A study showed that 50% of the tumour growth was inhibitedby 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 canbe targeted for better drug delivery using multi spectral opto-acoustictomography (MSOT and thernostic nanoparticles and fluorescent dyes. Colloidlemesoporous silica nanoparticles (CMS) were synthesis conjugative with V7peptide. These particles were analysed by using transmission electronmicroscopy and accumulation of these particles were observed.

Thesenanoparticles can be used to identify pancreatic tumour with high sensitivityand specificity for targeted drug delivery. 

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