Molecular therapeutics in pancreas cancer

Table 1 Barriers to effective molecularly targeted therapy in pancreatic ductal adenocarcinoma

PDAC biology	Barrier
Genetic heterogeneity	Inability to directly inhibit KRAS
	Convergence of signal transduction pathways downstream from KRAS with feedback inhibitory loops
Overexpression of EGFR, IGF-1R	Escape from growth factor dependence in later stages of tumorigenesis
Desmoplastic stroma	Hypoxic tumor milieu impairs effective drug delivery
Overexpression of angiogenic factors	Secretion of angiostatic factors in tumor microenvironment
PDAC stem cells	Difficult to eradicate subpopulation of cells capable of self-renewal Resistance to chemotherapy, radiation
Low immunogenicity	Evasion of host immunity Abundance of immunosuppressive cells in tumor milieu

PDAC: Pancreatic ductal adenocarcinoma; KRAS: Kirsten rat sarcoma oncogene; EGFR: Epidermal growth factor receptor; IGF-1R: Insulin like growth factor-1 receptor.

Table 2 Frequency and consequences of common genetic mutations in pancreatic ductal adenocarcinoma

Mutation category	Frequency in PDAC	Effects of mutation	Consequence
Gain of function
KRAS	> 95%	Continuous transduction of downstream growth signals (BRAF/MAPK, PI3K/mTOR)	Enhanced cell growth and survival
Loss of function
CDKN2A	95%	Disruption of RB1 by CDK4	Uncontrolled cellular proliferation
TP53	75%-85%	Impaired DNA damage repair, loss of cell cycle checkpoint activation	Chromosomal instability, aneuploidy
DPC4/SMAD4	50%	Loss of inhibition of TGF-β	Loss of cell growth inhibition
BRCA2	6%-17%	Impaired DNA damage repair by homologous recombination, loss of cell-cycle checkpoint activation	Genomic instability
PALB2	1%-3%	Impaired BRCA2 function	Genomic instability

KRAS: Kirsten rat sarcoma oncogene; BRAF: Rapidly activated fibrosarcoma homolog B; MAPK: Mitogen activated protein kinase; PI3K: Phosphatidyl inositol-3 kinase; mTOR: Mammalian target of rapamycin; CDK: Cyclin dependent kinase; DPC4: Deleted in pancreatic cancer 4; TGF-β: Transforming growth factor-β; BRCA2: Breast cancer 2; PALB2: Partner and localizer of BRCA.

Table 3 Summary of selected ongoing clinical trials evaluating molecular therapies in pancreatic ductal adenocarcinoma (according to http://www.clinicaltrials.gov, accessed July 2015)

Category	Clinical trial number	PDA setting	Medications studied	Phase	Status	Estimated completion
Tumor suppressor genes
	NCT01585805	Locally advanced/metastatic	Gem and Cisplatin ± Veliparib vs Veliparib alone	II	Recruiting	07/2017
	NCT01296763	Advanced	Irinotecan + Cisplatin + Mitomycin C ± Olaparib	I/II	Ongoing, not recruiting	01/2014
Recombinant hyaluronidase
	NCT01959139	Metastatic	FOLFIRINOX ± PEGPH20	I/II	Recruiting	12/2017
	NCT01839487	Metastatic	Gem + Nab-paclitaxel vs Gem + Nab-paclitaxel + PEGPH20	II	Recruiting	04/2016
Vaccine therapy
	NCT02004262	Metastatic	Cy + GVAX + CRS-207 vs Chemotherapy vs CRS-207	II	Recruiting	12/2016
	NCT01072981	Adjuvant	Chemotherapy vs Chemo-radiotherapy ± Algenpantucel-L	III	Ongoing, not recruiting	06/2016
	NCT01836432	Neoadjuvant	FOLFIRINOX ± Algenpantucel-L	III	Recruiting	09/2015
Immune checkpoint	NCT02472977	Metastatic	Ulocuplumab (CXCR4) and nivolumab (PD1)	IB	Recruiting	7/2017
CAR-T cell therapy
	NCT01897415	Metastatic	Autologous redirected RNA mesothelin specific CAR-T cells	I	Not recruiting	01/2015
	NCT01583686	Metastatic	CAR-T cell receptor	I/II	Recruiting	12/2018
Micro-RNA-21 targeted therapy
	NCT01274455	Locally advanced	Gem + Plasmid DNA CYL-02	I	Not recruiting	12/2013
Signal transduction inhibitors
Janus kinase targeted	NCT02119663	Locally advanced/metastatic	Capecitabine + Ruxolitinib vs Capecitabine + Placebo	III	Recruiting	06/2017
	NCT02117479	Locally advanced/metastatic	Capecitabine + Ruxolitinib vs Capecitabine + Placebo	III	Recruiting	12/2015
Wnt targeted	NCT02050178	Metastatic	OMP-54F28 + Gem-Nab-paclitaxel	I	Recruiting	12/2016
	NCT01764477	Metastatic	PRI-724 + Gem	I	Recruiting	03/2016
Notch inhibitor	NCT01647828	Locally advanced/metastatic	OMP-59R5 + Gem-Nab-paclitaxel	I/II	Recruiting	01/2016
TGF-β inhibitor	NCT01373164	Locally advanced/metastatic	LY2157299 + Gem	I/II	Not recruiting	11/2015

PDA: Pancreas ductal adenocarcinoma; Gem: Gemcitabine; FOLFIRINOX: 5-fluorouracil, leucovorin, irinotecan, oxaliplatin; CAR-T: Chimeric antigen receptor T cell; TGF-β: Transforming growth factor-β; Cy: Cyclophosphamide.