Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma
Abstract
:1. Introduction
2. Treatment Hurdles
3. Stem Cells
3.1. Cancer Stem Cells
3.2. Potential Approaches Targeting PCSCs
4. Signaling Pathways Involved in PCSCs
4.1. Notch Signaling Pathway
4.2. Hedgehog Signaling Pathway
4.3. WNT Signaling Pathway
5. Epithelial to Mesenchymal Transition
6. Role of Epigenetics
7. Role of G Protein-Coupled Receptor in Pancreatic Cancer
8. Role of Cysteine in Pancreatic Cancer
9. Role of Pyruvate Kinase M2
10. Repurposed Drugs for CSCs
11. Immunotherapy for Pancreatic Cancer
- Monotherapy includes the administration of several PD-1(MEDI4736, MPDL3280A, and pembrolizumab,) and CTL-4 (tremelimumab and ipilimumab) inhibitors and inhibition of double checkpoints: either by a combination of the above mentioned inhibitors or with other agents, such as anti-CCR-5 (mogamulizumab) [184].
- Combination of chemotherapeutic agents and immune checkpoint inhibitors: PD-1/CTL4 inhibitors leads to the activation of T cell that is efficient for immunotherapy. When PD-1/CTL4 inhibitors combined with commonly used chemotherapeutic agents such as Nab-paclitaxel, gemcitabine, carboplatin, and FOLFOX improved overall survival [47]. Remarkably, therapeutic procedures using a combination of immune checkpoint inhibitors with radiotherapy or chemotherapy have shown significant outcomes [185,186].
- Vaccination therapy is founded on the basis of the distribution of tumor antigens to antigen presenting cells (APCs), followed by induction of an organized immune response. Cancer specific DNA mutations produce new antigens, which, in turn, results in a unique sequence of the peptide. Variety of vaccines for pancreatic cancer treatment includes whole-cell vaccines, dendritic-cell based vaccines, peptide and DNA vaccines, telomerase peptide vaccines, Ras peptide vaccines, and survivin-targeted vaccines [187]; however, regardless of the enhanced immune system, showed poor clinical results. GVAX is an allogeneic irradiated whole-cell tumor vaccine genetically modified for the secretion of granulocyte macrophage colony stimulating factor and promotes cytolytic action against tumors, the most widely studied vaccine for pancreatic cancer [188]. Furthermore, the clinical studies when GVAX is applied in combination with 5-Fluorouracil/cyclophosphamide based chemotherapy have shown the same results regarding disease-free and median survival as that of GVAX applied alone [189]. On the other hand, when the above mentioned ipilimumab (immune checkpoint inhibitor) is applied in combination with GVAX, it leads to better survival [190].
- Adoptive T cell immunotherapy is based on the modification of autologous T cells, which stimulates the immune response against the tumor. The patients receiving mesothelin-targeting chimeric antigen receptor-T (CAR) cells have shown overexpression of a membrane antigen in pancreatic cancer, exhibited adequate patience but unsuccessful in showing good results [191]. Along with mesothelin, other cancer-associated antigens are being studied alone or in combination with chemotherapy as potential targets of CAR-T cells based therapy [191].
- Immune modulating agents that target the microenvironment of the pancreas can also exert extensive antitumor activity. Anti-CD40 agonistic antibodies used in combination with gemcitabine in PDAC patients showed significant results [192]. PDAC patients treated with a CCR2 inhibitor (PF-04136309) exhibited fractional response and constant tumor when used in combination with FOLFIRINOX [193]. Several chemokine receptor molecules are under examination in clinical trials against PDAC.
12. Natural Killer Cell Therapy
13. Discussion
14. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
CSCs | Cancer stem cells |
EMT | Epithelial mesenchymal transition |
ESCs | Embryonic stem cells |
GPCR | G protein-coupled receptor |
GPER | G protein-coupled estrogen receptor |
MSCs | Mesenchymal stem cells |
NK cell | Natural killer cells |
PCSCs | Pancreatic cancer stem cells |
PDAC | Pancreatic ductal adenocarcinoma |
PKM2 | Pyruvate kinase M2 |
PMCA | Plasma membrane calcium pump |
ROS | Reactive oxygen species |
SHH | Sonic Hedgehog |
Xc- | Cystine/glutamate transporter |
ZEB | Zinc-finger E-box binding homeobox |
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Drug | Structure | Pathway inVolved | Mechanism of Action | Accession Number | References | |||||
---|---|---|---|---|---|---|---|---|---|---|
Salinomycin | WNT/EMT | Inhibits the growth of CSCs | DB11544 | [42] | ||||||
Nigericin | EMT | Inhibit the cell viability | DB14056 | [43] | ||||||
Azithromycin | Mitochondria | Inhibiting protein synthesis and translation | DB00207 | [44] | ||||||
Chloroquine | OXPHOS | Inhibits the autophagy pathway | DB00608 | [45] | ||||||
Aspirin | ALDH1, NF-κB | Blocks prostaglandin synthesis | DB00945 | [46] | ||||||
Disulfiram | WNT, β-catenin and NF-κB | Induce apoptosis in cancer stem cells | DB00822 | [47] | ||||||
Aprepitant | WNT | Inhibit emesis induced by cytotoxic chemotherapeutic agents | DB00673 | [48] | ||||||
Atovaquone | HER2/β-catenin | Antiprotozoal, antimicrobial and antipneumocystis activity | DB01117 | [49] | ||||||
AZD8055 | mTOR | Activation of epidermal growth factor receptor | DB12774 | [50] | ||||||
Crocetinic acid | Hedgehog | Inhibited epidermal growth factor receptor and Akt phosphorylation | NA | [51] | ||||||
GANT-61 | Hedgehog | Inhibited cell viability. protects autophagy | NA | [52] | ||||||
Ketamine | WNT | Inhibiting proliferation, invasion, and migration | DB01221 | [53] | ||||||
Metformin | mTOR, PI3K/Akt | Antineoplastic activity | DB00331 | [54] | ||||||
Quinomycin A | Notch | Suppresses CSCs growth | DB15582 | [55] | ||||||
Rapamycin | mTOR | Reduced the viability of CSCs | DB00877 | [56] | ||||||
RO-4929097 | Notch | Suppresses the tumor initiating potential of cancer cells | DB11870 | [57] | ||||||
Sanguinarine | Hedgehog | Inhibits the growth of CSCs | NA | [58] | ||||||
Tigecycline | OXPHOS | Inhibits cell proliferation, migration and invasion | DB00560 | [59] | ||||||
5-FU (Fluorouracil Injection) | Antineoplastic antimetabolite | Inhibition of the formation of thymidylate from uracil | DB00544 | [60] | ||||||
Mitomycin | Antineoplastic antibiotic | Alkylating agent which inhibits DNA synthesis | DB00305 | [60] | ||||||
Abraxane/Paclitaxel | Microtubule associated protein | Stabilizes microtubules by preventing depolymerization | DB01229 | [61] | ||||||
Gemcitabine Hydrochloride/Gemzar | Antineoplastic anti-metabolite | Inhibits thymidylate synthetase | DB00441 | [61] | ||||||
Afinitor/Everolimus | mTOR inhibition | Immunosuppressant | DB01590 | [62] | ||||||
Erlotinib Hydrochloride/Tarceva | Epidermal growth factor receptor (EGFR) | Inhibits the intracellular phosphorylation of tyrosine kinase | DB00530 | [63] | ||||||
Lynparza/Olaparib | Poly (ADP-ribose) polymerase (PARP) inhibitor | Inhibit growth of tumor cells | DB09074 | [64] | ||||||
Onivyde/Irinotecan | Antineoplastic enzyme inhibitor | Inhibits the action of topoisomerase I | DB00762 | [65] | ||||||
Sunitinib Malate/Sutent | Multi-targeted receptor tyrosine kinase (RTK) inhibitor | Inhibits cellular signaling by targeting multiple RTKs | DB01268 | [66] |
Drug | Accession Number | Function | Mechanism of Action |
---|---|---|---|
FOLFIRINOX | |||
FOL: Folinic acid/Leucovorin | DB00650 | Antidote | Enhances the effects of 5-fluorouracil |
F: Fluorouracil | DB00544 | Pyrimidine analog and antimetabolite | Inhibit DNA synthesis |
IRIN: Irinotecan/Camptosar | DB00762 | Topoisomerase inhibitor | Prevents DNA from uncoiling and duplicating |
OX: Oxaliplatin/Eloxatin | DB00526 | Platinum-based antineoplastic agent | Inhibits DNA repair and synthesis |
GEMCITABINE-OXALIPLATIN | |||
Gemcitabine | DB00441 | Antineoplastic anti-metabolite | Inhibits thymidylate synthetase |
Oxaliplatin | DB00526 | Platinum-based antineoplastic agent | Inhibits DNA repair and synthesis |
GEMCITABINE-CISPLATIN | |||
Gemcitabine | DB00441 | Antineoplastic anti-metabolite | Inhibits thymidylate Synthetase |
Cisplatin | DB00515 | Antineoplastic | Alkylating agents |
OFF | |||
O: Oxaliplatin | DB00526 | Platinum-based antineoplastic agent | Inhibits DNA repair and synthesis |
F: Fluorouracil | DB00544 | Antineoplastic antimetabolite | Inhibition of the formation of thymidylate from uracil |
F: Folinic Acid/Leucovorin | DB00650 | Antidote | Enhances the effects of 5-fluorouracil |
Pathological Condition | Enrolled Patients | Intervention | National Clinical Trial Number | Outcome Measures | Phase | Status | Result |
---|---|---|---|---|---|---|---|
Neoplasms, Pancreas | 40 | Cancer stem cell vaccine | NCT02074046 | Determine the safety of immunization | Phase 1/2 | Completed | CTLs harvested from CSC-vaccinated hosts were capable of killing CSCs in vitro |
Metastatic pancreatic cancer | 98 | Gemcitabine, Nab-Paclitaxel, GDC-0449 | NCT01088815 | Progression free survival, safety of combination therapy | Phase 2 | Completed | Median progression-free survival and overall survival were 5.42 months and 9.79 months, respectively |
Metastatic pancreatic adenocarcinoma | 139 | BBI608 either in combination with Gemcitabine and nab-Paclitaxel, mFOLFIRINOX, FOLFIRI, or MM-398 with 5-FU and Leucovorin | NCT02231723 | Safety, Adverse effects | Phase 1 | Completed | Inhibit cancer stemness pathways, including Nanog, by targeting stemness kinases. |
Metastatic Pancreatic Ductal Adenocarcinoma | 65 | MEDI4736 Monotherapy, Tremelimumab + MEDI4736 | NCT02558894 | Response Rate, Overall survival, progression free survival, | Phase 2 | Completed | Monotherapy reflected a population of patients with mPDAC who had poor prognoses and rapidly progressing disease |
PDAC, Pancreatic Cancer | 21 | Ipilimumab, Gemcitabine hydrochloride | NCT01473940 | Overall survival, progression free survival, recovery of tumor immune surveillance | Phase 1 | Completed | Median progression-free and overall survival were 2.78 months and 6.90 months, respectively. |
Second-line, third-line and Greater Metastatic Pancreatic Cancer | 303 | GVAX Pancreas Vaccine, CRS-207, Chemotherapy, Cyclophosphamide | NCT02004262 | Overall survival and adverse effects | Phase 2 | Completed | Median overall survival in the primary cohort was 3.7, 5.4, and 4.6 months in arms A, B, and C, respectively (*) |
Pancreatic Neoplasm | 22 | Monoclonal antibody, chemotherapy | NCT00711191 | Overall survival, progression free survival, and time to Progression | Phase 1 | Completed | Well tolerated and associated with antitumor activity in patients with PDAC and improved overall survival |
Pancreatic Adenocarcinoma metastatic | 10 | Melphalan, BCNU, Vitamin B12, Vitamin C, and autologous hematopoietic stem cell | NCT04150042 | Response rate in metastatic lesions, overall survival, progression free survival | Phase 1 | Ongoing | NA |
Resectable pancreatic adenocarcinoma | 42 | HIPEC-Gemcitabine | NCT03251365 | Morbidity, survival | Phase 2/3 | Ongoing | NA |
PDAC, pancreatic cancer, metastasis | 36 | Ascorbic acid, Paclitaxel, Cisplatin, Gemcitabine | NCT03410030 | Determination of preliminary efficacy | Phase 1/2 | Ongoing | NA |
Pancreatic Cancer | 81 | Pembrolizumab, Gemcitabine, Docetaxel, Nab-paclitaxel, Vinorelbine, Irinotecan, Liposomal Doxorubicin | NCT02331251 | Determine the recommended phase 2 dose | Phase 1/2 | Terminated | The median progression-free survival and overall survival was 9.1 and 15.0 months, respectively |
Pancreatic Cancer | 15 | Fludarabine, Anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL), Cyclophosphamide, Aldesleukin | NCT01583686 | Tumor regression response and adverse effects | Phase 1/2 | Terminated | MORAb-009 (chimeric monoclonal antibody) is well tolerated |
Pancreatic adenocarcinoma | 10 | Allogeneic hematopoietic stem cell transplantation | NCT02207985 | Disease free survival | Phase 1/2 | Unknown | Patients are tumor-free for 9 years after diagnosis |
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Thakur, G.; Kumar, R.; Kim, S.-B.; Lee, S.-Y.; Lee, S.-L.; Rho, G.-J. Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma. Biomedicines 2021, 9, 178. https://doi.org/10.3390/biomedicines9020178
Thakur G, Kumar R, Kim S-B, Lee S-Y, Lee S-L, Rho G-J. Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma. Biomedicines. 2021; 9(2):178. https://doi.org/10.3390/biomedicines9020178
Chicago/Turabian StyleThakur, Gitika, Raj Kumar, Saet-Byul Kim, Sang-Yeob Lee, Sung-Lim Lee, and Gyu-Jin Rho. 2021. "Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma" Biomedicines 9, no. 2: 178. https://doi.org/10.3390/biomedicines9020178