1. Nab-paclitaxel is effective for intrahepatic cholangiocarcinoma via disrupting desmoplastic stroma
Chun-Yi Tsai3, Peter Mu-Hsin Chang1,2, Chi-Tung Cheng3, Ren-Chin Wu4, Yi-Hsiu Chung5, Kun-Chun Chiang3, Ta-Sen Yeh3 , Meng-Lun Lu1, Chun-Yu Liu1,2, Ming-Han Chen1, Ming-Huang Chen1,2* , Chun-Nan Yeh3
1Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
2School of Medicine, National Yang-Ming University, Taipei, Taiwan
3Department of Surgery, Liver Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
4Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
5Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Taoyuan, Taiwan

2. Intrahepatic chlangiocarcinoma
Malignant epithelial tumor originated from biliary tract within hepatic parenchyma.
2nd primary hepatic tumors
Poor outcome and prognosis without efficient adjuvant therapies
For unresectable IH-CCA:
1st line palliative regimen: cisplatin + gemcitabine
Limited responds
Khan SA, et al, Lancet, 2005
Valle J, et al, N Eng J Med, 2010

3. Multi-drug resistance of ih-cca
Possible explanation: desmoid pattern in liver parenchyma
IH-CCA is well-known for its desmoplastic and hypoplastic stroma, which are both predictive factors for poor drug penetration and response
α-smooth muscle actin (α-SMA) expressed by cancer- associated fibroblast (CAF)
Changing tumor microenvironment by increasing production of extracellular matrix proteins, cytokines, and growth factors that interact with CCA
Enhance tumor aggressive behavior as well as therapeutic resistance.
Sirica AE, et al, Hepatologyt, 2014

4. Cancer-associated fibroblasts (CAF)
Several CAF associated liver parenchyma diseases have been linked with the risk of CCA
Primary sclerosing cholangitis (PSC)
chronic bile duct inflammatory disease with fibrosis within biliary tract
A predisposing factor of IH-CCA with increasing α-SMA immunohistochemically staining over stroma.
Liver cirrhosis due to the chronic damage by toxic agents in animal models also suggests the close relationship between desmoplastic change and carcinogenesis of CCA
DeClerck YA, et al, Cancer Discov. 2012

5. Nab-paclitaxel Nanoparticle albumin-bound paclitaxel
Nab-paclitaxel had stromal disrupting effect in pancreatic cancer
Nab-paclitaxel plus gemcitabine had superior outcome than gemcitabine alone
Alvarez R, et al, Br J Cancer, 2013
Von Hoff DD, et al, N Engl J Medt, 2013

6. Aims Concept IH-CCA is also a desmoplastic tumor
The inhibitory effects of paclitaxel and nab-paclitaxel for different CCA cell lines
we used our established animal model with toxin-induced IH-CCA to perform the in vivo anti-tumor test for currently standard gemcitabine/platinum vs. paclitaxel vs. nab-paclitaxel

7. Rat orthotopic tumor graft
Yeh CN, et al, Carcinogenesist, 2004

8. Nab-paclitaxel showed similar anti-proliferative effects with paclitaxel in vitro
Human CCA cell lines
KKU-100 and KKU-213
MTT test showed similar cytotoxicity for both compounds in two different cell lines

9. Nab-paclitaxel showed similar anti-proliferative effects with paclitaxel in vitro
Nab-paclitaxel treatment resulted in a concentration-dependent increase in apoptosis percentage within 48 h: 54.32% of KKU100 and 60.78% of KKU213 cells were found apoptotic after treating with 20 nM of nab- paclitaxel

10. Anti-tumor effect of nab-paclitaxel is better than palcitaxel in TAA induced IH-CCA rat animal model
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5 SD rats in each group
Control, GEM/Oxa, Paclitaxel, Nab-paclitaxel
Treatment started at 21st week
PET scan at 21st, 23rd, 25th week
Each group showed at least one FDG-avid tumor in the liver after 20 weeks of TAA treatment
The change of tumor-to-liver (T/L) ratio is evaluated

11. Anti-tumor effect of nab-paclitaxel is better than palcitaxel in TAA induced IH-CCA rat animal model
dwdw
The T/L ratio of the SUV showed a mild increase until the final scans in paclitaxel treatment group
In the nab-paclitaxel and gemcitabine /oxaliplatin treatment group, the T/L ratio of the SUV showed a decrease until the final scans
only nab-paclitaxel treatment induced a significant decrease in T/L ratio of the SUV when compared with the control group
nab-paclitaxel treatment resulted in significant suppression of in vivo tumor growth in a model of rat CCA

12. Nab-paclitaxel disrupt cancer associated fibroblasts in rat intrahepatic CCA but not paclitaxel
4 weeks after treatment
The red-stained α-SMA was stronger and complete on paclitaxel- treated tumor when compared with the weak, dispersed staining over nab-paclitaxel treated tumor
The anatomical relationship between the CAFs (with α-SMA staining), vessels, and IH-CCA

13. Discussions In out rat model:
multifocal bile ductal proliferation with demonstrable atypia in the liver of the rat after the 9th weeks of administrate TAA
50% of rats develops IH-CCA with intense stromal desmoplasia since 16th weeks
From the 16th to 22th week, the incidence of invasive CCAs increased progressively to 100% of rats
A powerful pre-clinical platform for therapeutic strategies for human CCA
Yeh CN, et al, Carcinogenesist, 2004

14. Discussions
Both paclitaxel and nab-paclitaxel had similar anti-proliferative effect on two human CCA cell lines through apoptosis
By a significant decrease in T/L ratio of the SUV:
Nab-paclitaxel had anti-tumor effect in vivo in TAA animal model
Paclitaxel did not show anti-tumor effect in vivo in TAA animal model

15. Discussions
The effectiveness of Nab-paclitaxel can be explained at least partially, by the stromal disrupting effect
The stromal disrupting effect was only observed in nab-paclitaxel group
The current clinical observation also supported the above result and explained why paclitaxel has been proved with no treatment activity in biliary tract cancer since 1996

16. Discussions Limitations:
May not totally reflect the condition of human CCA
 this model overcame the difficulty that xenograft CCA model lacking surrounding CAFs
The small number of the 4 different treatment groups of rat may lower the statistical power
The animal PET revealed significantly inhibitory effect of nab- paclitaxel than paclitaxel but the immunofluorescence study could not show statistically significant difference between both treatments

17. Thanks for your attention