Pancreatic Cancer Research Pipeline of New Treatment Options

Pancreatic Cancer Research
Pipeline of New Treatment Options
Derek W Louden MA (Abdn.), MA (Shef.), MEI
Tel: 07876 774412
Email: LoudenDW@aol.com

William Louden (1936-2016)
Rest In Peace Dad

WARNING
I’m not a doctor. I have had no medical training.
I’ve written this PowerPoint for people with pancreatic
cancer and for their family members who will do what I
did and spend months trying to find a cure for my father.
My intention is to help you by pointing out a few places to
look.
I found some things which work with standard chemo
regimes. Talk to your doctor / oncologist prior to trying any
of them. If they say “no” listen.
I also found some things which were tantalisingly close to
being available. They could be available now. You should
also look for developments after I stopped looking in May
2016. I wish every one of you the very best of luck.

Pancreatic Cancer has one of the worst prognoses of any cancer.
The survival times haven’t improved much in 40 years.
Pancreatic Cancer Grows
 Tumours grow within and around vital organs
Pancreatic Cancer Spreads
 Cancer cells detach from the original tumour and migrate via a process known
as Metastasis (Mets) to other sites around the body.
Current treatment can delay, but isn’t able to prevent, Mets
http://www.pathpedia.com/education/eatlas/histopatholog
y/pancreas/ductal_adenocarcinoma,_nos/pancreatic-ductal-
adenocarcinoma-%5B3-
pn004_1%5D.jpeg?Width=600&Height=450&Format=4

Current Research for Improved Survival Rates
We’ll Look at the Following clinical studies
Metformin – not recommended
siG12D-LODER releases siRNA to knock down YAP1
miR-375 to target 3’UTR of YAP1 mRNA
Snail regulated miR-375 targeting JAK2
Peptide Mimicking VGLL4
PEGPH20 ablates Stromal HA
QD232 Targeting Src/FAK and STAT3 signalling
Cilengitide & Verapamil combination therapy with Gemcitabine
C19 Small Molecule inhibitor of Hippo, TGF-B and Wnt
Vitamin D Receptor-Mediated Stromal Reprogramming
THERACURMIN® (Curcumin)
 Minnelide (Triptolide)
Salinomycin
Protein Kinase D1
QS molecule O-DDHSL
interleukin-10 (IL-10) gene
And new Delivery Method
Polymeric Micelles for Salinomycin delivery

Metformin
Metformin
 Theory
Metformin would use its antineoplastic properties to target the Stroma to ablate
this physical barrier to Chemo extending survival time for patients.
 Result
A recent study in The Lancet showed Metformin did not improve the survival
prospects of patients with advanced pancreatic cancer. Indeed 63.9% of the
placebo group on Gemcitabine and Erlotinib survived 6 months whereas only
56.7% of the group given Metformin along with Gemcitabine and Erlotinib were
still alive.

Metformin
Metformin
 Results showed Epithelial-Mesenchymal Transition isn’t slowed:
Source: “Epithelial–mesenchymal plasticity in carcinoma metastasis”, Jeff H. Tsai and Jing Yang
Department of Pharmacology, Department of Pediatrics, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA
http://genesdev.cshlp.org/content/27/20/2192.full.pdf+html

Metformin
Metformin
 Conclusion
Metformin was thought to protect patients by allowing Chemo to get through the
stroma to attack the Cancer. What seems to have happened is that the process of
weakening the stroma has the result of allowing the latter stages of Cancer
progression to proceed faster than the Gemcitabine can counteract it.
This suggests that badly damaging the stroma isn’t a good idea as the stroma acts
to protect the patient from the invasion of metastatic cancer. An alternative
method is needed to get the Gemcitabine past the stroma without so weakening
it as to leave it open to metastatic attack.

Suppressing YAP and the p53 oncogene
Pancreatic Cancer - Suppressing YAP and the p53 oncogene
 Gene Therapy for Pancreatic Tumours
A team at Georgetown Lombardi Comprehensive Cancer Center in Washington
led by Prof. W Zhang and Associate Prof. Chunling Yi has published a study
showing that inhibiting a single protein completely shuts down growth of
Pancreatic Cancer. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175524/
http://www.ncbi.nlm.nih.gov/pubmed/24803537
Around 95% of patients are found to have a KRAS gene mutation and 75% have a
P53 gene mutation. Suppressing a protein known as YAP didn’t stop the cancer
developing but it did stop it progressing. Suppressing YAP also shuts down the
activity of the p53 oncogene.
Schematic of the function of YAP in PDAC cells as a master
transcriptional switch of the KRAS secre-tome promoting
PDAC cell proliferation.
Downstream of Mutant KRAS, the Transcription Regulator YAP Is Essential for
Neoplastic Progression to Pancreatic Ductal Adenocarcinoma
Weiying Zhang, Nivedita Nandakumar, Yuhao Shi, Mark Manzano, Alias Smith,
Garrett Graham, Swati Gupta, Eveline E. Vietsch, Sean Z. Laughlin, Mandheer
Wadhwa, Mahandranauth Chetram, Mrinmayi Joshi, Fen Wang, Bhaskar Kallakury,
Jeffrey Toretsky, Anton Wellstein, and Chunling Yi*
Sci Signal. ; 7(324): ra42. doi:10.1126/scisignal.2005049
www.sciencesignaling.org/cgi/content/full/7/324/ra42/DC1
Correspondence: cy232@georgetown.edu

siG12D-LODER
siG12D-LODER™ Biodegradable implant
 Theory
A siRNA drug would be used against KRAS(G12D) which is subject to a genetic
mutation in 90% of Pancreatic Ductal Adenocarcinoma cases.
 Action
A miniature biodegradable implant siG12D-LODER™ was inserted into a tumour
and released a siRNA drug against KRAS(G12D) over four months.
 Result
Patient survival times were significantly improved.
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=4183
Talia Golan, email: Talia.Golan@sheba.health.gov.il

What current research is there?
Pancreatic Cancer - miR-375
 Gene Therapy for Pancreatic Tumours - miR-375
A team from the Laboratory of Animal Development Biology, College of Life
Science, Northeast Forestry University, Hexing Road, Harbin, China under ZW
Zhang found that YAP1 was highly expressed in embryonic and adult pancreatic
progenitor cells. Knocking down YAP1 by siRNA inhibited the proliferation of
pancreatic progenitor cells. miR-375 targeted the 3' UTR of YAP1 mRNA to
decrease its protein and mRNA levels. Similar to silencing YAP1 by siRNA, the
proliferation of pancreatic progenitor cells was inhibited significantly by miR-375.
miR-375 Inhibits Proliferation of Mouse Pancreatic Progenitor Cells by Targeting YAP1
Zhang Z.-W. · Men T. · Feng R.-C. · Li Y.-C. · Zhou D. · Teng C.-B.
Cell Physiol Biochem 2013;32:1808-1817 (DOI:10.1159/000356614)
Chun-Bo Teng
Laboratory of Animal Development Biology, College of Life Science, Northeast Forestry
University, No.26 Hexing Road, Harbin 150040 (China)
Fax +86-451 -82191784, E-Mail chunboteng@nefu.edu.cn
http://www.karger.com/Article/FullText/356614

miR-375 to target 3’UTR of YAP1 mRNA
 miR-375
miR-375 works like siRNA to inhibit the proliferation of pancreatic progenitor cells
– or cancer stem cells (CSCs).
https://en.wikipedia.org/wiki/Mir-375
miR-375 has been found significantly downregulated in multiple
types of cancer, and suppresses core hallmarks of cancer by
targeting several important oncogenes like AEG-1, YAP1, IGF1R
and PDK1. Expression levels of JAK2 and miR-375 are inversely
correlated in GC tissues.
“The Emerging Role of miR-375 in Cancer”
Jun-Wei Yan, Ju-Sheng Lin and Xing-Xing H
Int J Cancer. 2014 Sep 1;135(5):1011-8. doi: 10.1002/ijc.28563. Epub 2013 Nov 13.

Pancreatic Cancer -
 Gene Therapy for Pancreatic Tumours 3
MicroRNAs are being investigated by a team under Jun Wei Yan at the Institute of
Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of
Science and Technology, Wuhan, China. miR-375 is a multi-functional miRNA
which is significantly downregulated in many types of cancer, including
pancreatic.
MiR-375 is significantly downregulated in multiple cancers and acts as a tumor
suppressor by targeting important oncogenes, such as AEG-1, PDK1, ATG7, IGF1R,
JAK2, 14-3-3Z, YAP1 and SP1. MiR-375 moderates cancer-related processes such
as cell proliferation, apoptosis, invasion and migration, metastasis and autophagy.
“The Emerging Role of miR-375 in Cancer” Jun-Wei Yan, Ju-Sheng Lin and Xing-Xing He
Int J Cancer. 2014 Sep 1;135(5):1011-8. doi: 10.1002/ijc.28563. Epub 2013 Nov 13.
E-mail: xxhe@tjh.tjmu.edu.cn or jslin@tjh.tjmu.edu.cn

“The Emerging Role of miR-375 in Cancer” Jun-Wei Yan, Ju-Sheng Lin and Xing-Xing He
Int J Cancer. 2014 Sep 1;135(5):1011-8. doi: 10.1002/ijc.28563. Epub 2013 Nov 13. http://www.ncbi.nlm.nih.gov/pubmed/24166096
E-mail: xxhe@tjh.tjmu.edu.cn or jslin@tjh.tjmu.edu.cn

Snail-Regulated MiR-375 Inhibits Migration and Invasion
of Gastric Cancer Cells by Targeting JAK2
 A further study of miR-375 looked at how it prevents migration and invasion of
Gastric Cancer Cells at least in part by targeting Janus Kinase 2 (JAK2)
miR-375 is regulated by and inversely correlated with Snail mRNA. Too much
Snail means miR-375 can no longer suppress JAK2 which allows Gastric Cancer
Cells to metastasise
 restoration of miR-375 or inhibition of Snail or JAK2 may be useful therapeutic
strategies for gastric cancer treatment
Xu Y, Jin J, Liu Y, Huang Z, Deng Y, et al. (2014) Snail-Regulated MiR-375 Inhibits Migration and Invasion of Gastric Cancer
Cells by Targeting JAK2. PLoSONE 9(7): e99516. doi:10.1371/journal.pone.0099516
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108470/

Peptide Mimicking VGLL4
Pancreatic Cancer - Peptide Mimicking VGLL4
Over-expression of YAP plays a key role in switching off defences against cancer
and in allowing cancer cells to start to spread.
The Hippo Pathway and YAP/TAZ–TEAD Protein–Protein Interaction as Targets for Regenerative Medicine and Cancer
Treatment
Matteo Santucci, Tatiana Vignudelli, Stefania Ferrari, Marco Mor, Laura Scalvini, Maria Laura Bolognesi, Elisa Uliassi, and Maria
Paola Costi
J. Med. Chem., 2015, 58 (12), pp 4857–4873
Publication Date (Web): February 26, 2015 (Perspective) DOI: 10.1021/jm501615v

Peptide Mimicking VGLL4
Pancreatic Cancer - Peptide Mimicking VGLL4
 The YAP TEAD interaction
A Chinese team has looked at peptides and has developed one called Super-TDU
which can mimick VGLL4 to compete with YAP for TEAD4 binding thus preventing
over-expression of YAP causing metastasis.
Jiao, S. et al. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 25,
166–180 (2014). 10.1016/j.ccr.2014.01.010
Correspondence: hbji@sibcb.ac.cn (H.J.), rayzhang@sibcb.ac.cn (L.Z.), zczhou@sibcb.ac.cn (Z.Z.)

PEGPH20 ablates Stromal HA
Pancreatic Cancer - PEGPH20 ablates Stromal HA
 PEGPH20 ablates Stromal HA
Halozyme Theraputics has developed a treatment which is beneficial for patients who
have high levels of hyaluronan (HA). PEGPH20 targets HA to help improve cancer
therapy access to tumor cells. HYLENEX® recombinant human hyaluronidase
 Result
In the 30 high HA patients who were evaluated for response prior to the April 2014
clinical hold and subsequent PEGPH20 treatment discontinuation, the overall response
rate was 73 percent. Study was halted due to “Thromboembolic Events” – strokes. Now
re-started.
Sunil Hingorani, M.D., Ph.D.,
Click here to for .pdf copy of the ASCO 2015 oral presentation.

QD232 Targeting Src/FAK and STAT3 signalling
Pancreatic Cancer - QD232 Targeting Src/FAK and STAT3 signalling
 QD232 Targeting Src/FAK and STAT3 signalling – Theory
Simultaneously targeting Src/FAK and STAT3 signalling could provide an important
strategy for treating pancreatic cancer.
Result
QD232 potently inhibited Src/FAK and STAT3 phosphorylation, decreasing pancreatic
cancer cell viability and migration. Furthermore, QD232 arrested cell cycle progression
and induced apoptosis in these cells at low micromolar concentrations.
Pathania, D., Kuang, Y., Sechi, M. and Neamati, N. (2015), Mechanisms underlying the cytotoxicity of a novel quinazolinedione-based
redox modulator, QD232, in pancreatic cancer cells. British Journal of Pharmacology, 172: 50–63. doi: 10.1111/bph.12855
http://onlinelibrary.wiley.com/doi/10.1111/bph.12855/abstract;jsessionid=49F90EC6FF2EC5B8ED1D48EB82DE0C8E.f04t01
Email: neamati@usc.edu or neamati@umich.edu or mario.sechi@uniss.it

Cilengitide & Verapamil combination therapy with Gemcitabine
Pancreatic Cancer - Cilengitide & Verapamil combination therapy with Gemcitabine
Theory
Cilengitide & Verapamil in combination with Gemcitabine might improve survival time.
Result
Combination Therapy with all three was indeed the best option.
Dual-Action Combination Therapy Enhances Angiogenesis while Reducing Tumor Growth and Spread
Ping-Pui Wong, Fevzi Demircioglu, Essam Ghazaly, Wasfi Alrawashdeh, Michael R.L. Stratford,
Cheryl L. Scudamore, Biancastella Cereser, Tatjana Crnogorac-Jurcevic, Stuart McDonald, George Elia,
Thorsten Hagemann, Hemant M. Kocher, and Kairbaan M. Hodivala-Dilke*
*Correspondence: k.hodivala-dilke@qmul.ac.uk

C19 Small Molecule Inhibitor of Hippo, TGF-B, and Wnt
Pancreatic Cancer - C19 Small Molecule Inhibitor of Hippo, TGF-B, and Wnt
Small Molecule Inhibitor of Hippo, TGF-B, and Wnt
A team at the University of Pittsburg including the inventor Abdelhadi Rebbaa has
developed a compound C19 with a powerful inhibitory effect on Hippo, Wnt and
TGF-B. Hadi is presently engaged in a funding round to build a Lab to continue his
work on C19, this time in the clinic. His patent application is in. C19 inhibited
tumour growth in a dose dependent manner with 20 mg/kg inducing approx
90% inhibition.
Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-b, and Wnt Signaling Pathways
Dipanjan Basu1, Robert Lettan3, Krishnan Damodaran2, Susan Strellec3, Miguel Reyes-Mugica1, and Abdelhadi Rebbaa1
http://mct.aacrjournals.org/content/early/2014/05/22/1535-7163.MCT-13-0918.full.pdf E-mail: abr25@pitt.edu

Modified Vitamin D – Stromal reprogramming with Calcipotriol
Pancreatic Cancer -
Modified Vitamin D treatment for Pancreatic Cancer
QMUL the vitamin D receptor (VDR) is expressed in stroma from human PDA
tumours. Treatment with the VDR ligand calcipotriol markedly reduced markers
of inflammation and fibrosis in pancreatitis and human tumour stroma. VDR acts
as a master transcriptional regulator of PSCs to reprise the quiescent state,
resulting in induced stromal remodeling, increased intratumoural gemcitabine,
reduced tumour volume, and a 57% increase in survival versus chemo alone.
Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses
Pancreatitis and Enhances Pancreatic Cancer Therapy
Mara H. Sherman, Ruth T. Yu, Dannielle D. Engle, Ning Ding, Annette
R. Atkins, Herve Tiriac, Eric A. Collisson, Frances Connor, Terry Van
Dyke, Serguei Kozlov, Philip Martin, Tiffany W. Tseng, David W.
Dawson, Timothy R. Donahue, Atsushi Masamune, Tooru
Shimosegawa, Minoti V. Apte, Jeremy S. Wilson, Beverly Ng, Sue
Lynn Lau, Jenny E. Gunton, Geoffrey M. Wahl, Tony Hunter, Jeffrey
A. Drebin, Peter J. O’Dwyer, Christopher Liddle, David A. Tuveson,
Michael Downes,* and Ronald M. Evans1,*
http://www.sciencedirect.com/science/article/pii/S0092867414010
332
Correspondence: downes@salk.edu (M.D.), evans@salk.edu
(R.M.E.)

Curcumin
Pancreatic Cancer - Combination treatment with Gemcitabine and Curcumin
 Combination treatment with Gemcitabine and Curcumin
A team from Ohio showed that this combination had a synergistic effect. Curcumin has
antioxidant and anti-inflammatory properties and has been shown to protect against
carcinogenesis and prevent tumour formation and development in several types of
cancer and also to suppress angiogenesis and metastasis in a variety of animal tumour
models.
Curcumin analogues exhibit enhanced growth suppressive activity in human pancreatic cancer cells
Lauren Friedman, Li Lin, Sarah Ball, Tanios Bekaii-Saab, James Fuchs, Pui-Kai Li, Chenglong Li, and Jiayuh Lin
Anticancer Drugs. 2009 July ; 20(6): 444–449. doi:10.1097/CAD.0b013e32832afc04
Correspondence to Jiayuh Lin, PhD lin.674@osu.edu
Due to poor bio-availability a concentrated form, Theracurmin, has been developed
by a team in Japan.
Curcumin and Pancreatic Cancer: A Research and Clinical Update
Carlos J. Díaz Osterman and Nathan R. Wall*
Journal of Nature and Science, 1(6):e124, 2015*Corresponding Author: Nathan R. Wall, Ph.D.,
http://www.jnsci.org/files/html/e124.htm
Email: nwall@llu.edu

Theracurmin
Pancreatic Cancer - Combination treatment with Gemcitabine and Theracurmin
 Combination treatment with Gemcitabine and Theracurmin
A team from Kyoto University Hospital led by Masashi Kanai identified the potential
theraputic benefits of curcumin. They next set to work on improving the bio-
availability of the agent by developing a concentrated version Theracurmin.
This has undergone clinical trials.
Result
Repetitive systemic exposure to high concentrations of curcumin achieved by
Theracurmin did not increase the incidence of adverse events in cancer patients
receiving gemcitabine-based chemotherapy.
A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in
cancer patients.
Kanai M, Otsuka Y, Otsuka K, Sato M, Nishimura T, Mori Y, Kawaguchi M, Hatano E, Kodama Y, Matsumoto S,
Murakami Y, Imaizumi A, Chiba T, Nishihira J, Shibata H,
Cancer chemotherapy and pharmacology. 2013;71(6):1521-30.
e-mail: kanai@kuhp.kyoto-u.ac.jp

Theracurmin
Pancreatic Cancer - Combination treatment with Gemcitabine and Theracurmin
 Phase II Trial with Gemcitabine and Theracurmin
Masashi Kanai tested the improved concentrated version Theracurmin in clinical trials.
 Results
Three patients safely continued THERACURMIN® treatment for > 9 mo
Fatigue and functioning-associated quality of life (QOL) scores scaled by EORTC QLQ-
C30 significantly improved following THERACURMIN® administration.
Curcumin may irritate the intestine, potentially increasing abdominal pain in
patients with intestinal obstructions due to peritonitis carcinomatosa or other
complications. These should be checked for by CT scan prior to commencement.
 future clinical trials should be cautious when administering curcumin to these types
of patients – CT scan first!
 THERACURMIN® treatment leads to better survival times by delaying EMT and
slowing down the rate of tumour growth.
Therapeutic applications of curcumin for patients with pancreatic cancer.
World J Gastroenterol 2014; 20(28): 9384-9391
Available from: URL: http://www.wjgnet.com/1007-9327/full/v20/i28/9384.htm
DOI: http://dx.doi.org/10.3748/wjg.v20.i28.9384
e-mail: kanai@kuhp.kyoto-u.ac.jp

Minnelide (Triptolide)
Pancreatic Cancer - Minnelide (Triptolide)
 Minnelide
A team at the University of Minnesota developed Minnelide as a soluble version of
Triptolide for use in trials.
 Results
All the mice treated with Minnelide survived until the end of the trial.
Minnelide, a novel drug for pancreatic and liver cancer
Sulagna Banerjee a, Ashok Saluja *
Pancreatology 15 (2015) S39eS43
http://www.pancreatology.net/article/S1424-3903%2815%2900573-6/abstract
E-mail address: asaluja@umn.edu (A. Saluja).
Minnelide activates two different cell death pathways: 1) apoptosis in MIA PaCa-2,
Capan-1, BxPC-3 cells and 2) autophagy in S2-013, S2-VP10, and Hs766T cells

Salinomycin
Pancreatic Cancer -
 Combination treatment with Salinomycin
A team led by Piyush B. Gupta published a paper in the Journal “Cell” setting out
their findings from screening a collection of 16,000 compounds.
http://www.cell.com/cell/issue?pii=S0092-8674%2809%29X0017-6
They found that Salinomycin an antibiotic used to treat cattle was lethal to
human Cancer Stem Cells (CSC) when tested on stem-like HMLER-shEcad cells.
Further research showed (Guan-Nan Zhang et al 2011) that a combination of
gemcitabine and salinomycin eliminates pancreatic cancer cells.
www.elsevier.com/locate/canlet or
Treatment has moved from in vitro to in vivo with a researcher from Germany
whose work we’ll look at next.

Salinomycin
Pancreatic Cancer - Salinomycin – How it Works
Salinomycin: A Novel Anti-Cancer Agent with Known Anti-Coccidial Activities
Shuang Zhou, Fengfei Wang, Eric T. Wong, Ekokobe Fonkem, Tze-Chen Hsieh, Joseph M. Wu, and Erxi Wu,*
Curr Med Chem. 2013 ; 20(33): 4095–4101. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102832/
Email: erxi.wu@ndsu.edu

Salinomycin
Pancreatic Cancer -
 Targeting Human Cancer Stem Cells (CSCs) with Salinomycin
A German team has treated patients with Salinomycin killing regular tumour cells,
highly indolent tumour cells and Cancer Stem Cells (CSCs). Traditional Pancreatic
treatment with chemotheraputic drugs such as Gemcitabine isn’t successful in
knocking down CSCs or in preventing metastases over prolonged periods of time.
The corresponding author is Cord Naujokat.
Patients with breast cancer, ovarian cancer, head cancer, neck cancer and cancer
of the vulva were all treated where conventional chemo and radiotherapy had
failed to kill Cancer Stem Cells (CSCs). All the patients treated had exhausted
other treatment options and had advanced metastatic cancers.
Salinomycin as a Drug for Targeting Human Cancer Stem Cells
Cord Naujokat and Roman Steinhart
Journal of Biomedicine and Biotechnology Volume 2012, Article ID 950658, 17 pages
doi:10.1155/2012/950658
http://www.hindawi.com/journals/bmri/2012/950658/
Prof. Cord Naujokat prof.naujokat@gmx.de or cord.naujokat@med.uni-heidelberg.de

Salinomycin
Pancreatic Cancer -
 Combination Therapy Gemcitabine with Salinomycin
A Chinese team has shown that combining Gemcitabine with Salinomycin kills
pancreatic cancer cells.
Combination of salinomycin and gemcitabine eliminates pancreatic cancer cells
Guan-Nan Zhang, Yi Liang, Ling-Jun Zhou, Shu-Peng Chen, Ge Chen,
Tai-Ping Zhang, Tiebang Kang, Yu-Pei Zhao *
Cancer Letters 313 (2011) 137-144 doi: 1 0.101 6/j.canlet.2011.05.030
http://www.cancerletters.info/article/S0304-3835%2811%2900307-7/abstract
E-mail address: zhao8028@263.net (Y.-P Zhao).
 Data indicated that SAL can inhibit pancreatic CSCs. More importantly, their
results indicated combined treatment of SAL and GEM eliminated both CSCs
and differentiated cells.

Salinomycin
Pancreatic Cancer - Salinomycin’s Modus Operandi
 Combination Therapy Gemcitabine with Salinomycin
Salinomycin triggers tumour cell apoptosis. Mechanisms involved include
mitochondrial & cellular K+ efflux with loss of K+, interference with mitochondrial
function caspase activation by the mitochondrial pathway, generation of reactive
oxygen species (ROS), endoplasmic reticulum stress, autophagy, inhibition of Akt
activation of p38 kinase and erythrocyte cell membrane scrambling.
Triggering of Erythrocyte Cell Membrane Scrambling by Salinomycin
Rosi Bissinger, Abaid Malik, Kashif Jilani and Florian Lang
Basic & Clinical Pharmacology & Toxicology, 2014, 115, 396–402 Doi: 10.1111/bcpt.12250
http://onlinelibrary.wiley.com/doi/10.1111/bcpt.12250/pdf
E-mail florian.lang@uni-tuebingen.de
Salinomycin specifically inhibits
the Wnt/β-catenin signaling
pathway initiated by Wnt1.
Salinomycin selectively inhibited Wnt
signaling mediated by Wnt1/Fzd5/LRP6

Protein Kinase D1
Pancreatic Cancer - Protein Kinase D1
Gene Therapy for Pancreatic Tumours - Protein
Kinase D1
A team from the US Mayo Clinic and the University
of Oslo under Dr. Peter Storz has identified a
molecule that makes normal pancreatic cells change
their shape. The gene found is known as protein
kinase D1 or PKD1. When they blocked PKD1
pancreatic progenitor cell production shown in the
production of duct-like cells and lesions decreased.
The model tells us that PKD1 is essential for the
initial transformation from acinar to duct-like cells.
Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia
Geou-Yarh Liou, Heike Döppler, Ursula B. Braun, Richard Panayiotou, Michele Scotti Buzhardt, Derek C. Radisky, Howard C.
Crawford, Alan P. Fields, Nicole R. Murray, Q. Jane Wang, Michael Leitges & Peter Storz
Nature Communications 6, Article number: 6200 doi:10.1038/ncomms7200
http://www.nature.com/ncomms/2015/150220/ncomms7200/pdf/ncomms7200.pdf#access
Email: Storz.Peter@mayo.edu

QS molecule O-DDHSL
Pancreatic Cancer - QS molecule O-DDHSL
 QS molecule O-DDHSL
The combined findings from a study by Ashwath Kumar’s group at the
Comparative Oncology and Epigenetics Laboratory, Veterinary Medicine and
Surgery, University of Missouri, Columbia, Missouri demonstrate that QS
molecule O-DDHSL decreases cell viability, promotes apoptosis by activating
caspases, and inhibits the wound healing process. O-DDHSL modulates genes
responsible for migration such as RhoC, cofilin and IQGAP-1. However, they
observed that O-DDHSL also affect some of the normal epithelial cells properties
similar to that of tumour cells, which could be a limiting factor when it comes to
the clinical application of this molecule. The potential for O-DDHSL as a possible
chemotherapeutic agent for pancreatic cancer needs further in vivo evaluation.
http://www.plosone.org/article/fetchObject.action?uri=info:doi/10.1371/journal.
pone.0106480&representation=PDF

QS molecule O-DDHSL
Panc-1 (66103 cells per well) was treated with different concentrations of O-DDHSL for 24 and 48
h. Significant decrease in cell viability was observed with 200–300 mM O-DDHSL (P#0.05) after 24
h. At 48 h, cell viability decrease was significant at ODDHSL concentration at or above 100 mM
(P#0.02; n = 3). However, HPDE cell viability was not affected after 48 h except for a slight
decrease at 300 mM O-DDHSL. No effect was observed with O-HHSL. B – Aspc-1 (66103 cells per
well) was more sensitive to O-DDHSL exposure than Panc-1. A significant decrease (P#0.02) was
observed in viability $25 mM O-DDHSL after 24 or 48 h (n = 3). Cell viability was not affected by
O-HHSL. In both cases, DMSO (0.02%) was used as diluent control which did not affect the cell
viability per se.
Bacterial Quorum Sensing Molecule N-3-Oxo-Dodecanoyl-L-Homoserine Lactone Causes Direct Cytotoxicity and Reduced
Cell Motility in Human Pancreatic Carcinoma Cells
Ashwath S. Kumar, Jeffrey N. Bryan, Senthil R. Kumar* doi:10.1371/journal.pone.0106480
http://www.plosone.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pone.0106480&representation=PDF
Email: kumars@missouri.edu

QS molecule O-DDHSL
Panc-1 cells were plated on a layer of matrigel in chamber slides in serum free
DMEM/F12 media and allowed to grow for two weeks. O-DDHSL (200 mM) was added
to the cells and incubated for 48 h at 37uC. Subsequently, a fluorescent dye Calcein
AM was added and further incubated for 2 h for its uptake by the cells. C–E –Light
Bacterial Quorum Sensing Molecule N-3-Oxo-Dodecanoyl-L-Homoserine Lactone Causes Direct Cytotoxicity and Reduced
Cell Motility in Human Pancreatic Carcinoma Cells
Ashwath S. Kumar, Jeffrey N. Bryan, Senthil R. Kumar* doi:10.1371/journal.pone.0106480
http://www.plosone.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pone.0106480&representation=PDF
Email: kumars@missouri.edu
microsopy pictures of cells growing on matrigel
before and after addition of O-DDHSL showing
morphological changes of apoptosis (toppanel).
Bottom panel shows the uptake of Calcein AM dye in
the cells before and after treatment with O-DDHSL,
showing dye uptake by viable cellsand loss of cell
viability resulting in the absence of dye uptake (406).

interleukin-10 (IL-10) gene
Pancreatic Cancer -
 Viro Therapy c/w Immunotherapy for Pancreatic Tumours
The QMUL team, at Barts Cancer Institute, armed the Vaccinia virus with a copy
of the interleukin-10 (IL-10) gene, which would express proteins in the cancer cell
once infected by the Vaccinia. Researchers hoped that this would allow the virus
to take hold and persist for longer. “Many viruses use IL-10 to hide from the
host’s immune system, so we thought we’d use this natural strategy to investigate
whether it would improve Vaccinia’s effectiveness,” said Dr Yaohe Wang, who led
the research. The results suggest that VVL∆TK-IL10 has strong potential as an
antitumor therapeutic for Pancreatic Cancer.
A Vaccinia virus armed with interleukin-10 is a promising therapeutic agent for treatment of murine pancreatic cancer
Louisa Chard1, Eleni Maniati2, Pengju Wang3, Zhongxian Zhang3, Dongling Gao3, Jiwei Wang3, Fengyu Cao4, Jahangir
Ahmed1, Margueritte EI Khouri1, Jonathan Hughes1, Shengdian Wang5, Xiaozhu Li6, Bela Denes7, Istvan Fodor8,
Thorsten Hagemann9, Nicholas R. Lemoine10, and Yaohe Wang1,* doi: 10.1158/1078-0432.CCR-14-0464
http://clincancerres.aacrjournals.org/content/early/2014/11/21/1078-0432.CCR-14-0464.abstract
Email: yaohe.wang@qmul.ac.uk
A transmission electron micrograph of
Vaccinia
(via CDC Public Health Image Library)

New delivery method – Polymeric Micelles of Salinomycin
Pancreatic Cancer -
 Targeting Pancreatic Cancer with Polymeric Micelles of Salinomycin
An Iranian team developed a technique to deliver Salinomycin in a better targeted way
using Polymeric Micelles. In gemcitabine-resistant AsPC-1 cells, SAL was found to
significantly increase cell mortality and apoptosis. It was also observed that SAL
micellar formulations inhibited invasion and harnessed EMT in spite of induced
expression of Snail. The in vivo anti-tumour experiment showed significant tumour
eradication and the highest survival probability in mice treated with SAL PMs. As with
Minnelide, 100% of the mice survived.
Polymeric Micelles of PEG-PLA Copolymer as a Carrier for Salinomycin Against Gemcitabine-Resistant Pancreatic Cancer
Zahra Daman, Hamed Montazeri, Masoumeh Azizi, Faegheh Rezaie, Seyed Nasser Ostad, Mohsen Amini, Kambiz GilaniPharm
Res (2015) 32:3756–3767 DOI 10.1007/s11095-015-1737-8
http://link.springer.com/article/10.1007%2Fs11095-015-1737-8
Email: Kambiz Gilani gilani@tums.ac.ir

Summary
Pancreatic Cancer -
 Present research on the Hippo pathway is summarised on the slide below
Hippo signaling pathway in liver and pancreas: the potential drug target for tumor therapy
Delin Konga, Yicheng Zhaoa, Tong Mena & Chun-Bo Tenga*
Journal of Drug Targeting Volume 23, Issue 2, 2015
http://www.tandfonline.com/doi/abs/10.3109/1061186X.2014.983522
E-mail: chunboteng@nefu.edu.cn

Pancreatic Cancer Research Pipeline of New Treatment Options

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