STATs are transcription factors which are normally present in the cytoplasm and activated by inflammatory signalling associated with epithelial to mesenchymal transition (EMT) which leads to their nuclear import . STAT3 expression is maintained and constitutive activation has been reported in at least 30% of pancreatic cancers .
Fatty acid synthase (FASN) is a key enzyme involved in lipogenesis and the production of long-chain fatty acids from acetyl-coenzyme A (CoA) and malonyl-CoA which is crucial for rapidly growing cancer cells including pancreatic . The inhibition of fatty acid synthase is known to increase reactive oxygen species (ROS) levels in cancer which is associated with apoptosis .
Focal Adhesion Kinase (FAK) inhibitors demonstrated in preclinical pancreatic cancer models increased mouse survival time via tumour stasis, reduced collagen deposition and reduced numbers of activated fibroblasts, down-regulated gene expression of fibrosis associated markers, reduced cancer stem-like cell numbers, reduced numbers of immunosuppresive cells within tumours, synergized with gemcitabine treatment, synergized with adoptive T cell transfer to reduce tumour volume and was associated with increased numbers of therapeutic T cell in the tumour and synergised with checkpoint inhibitors under certain circumstances .
|Figure 1: HO-3867 mechanisms of action in cancer cells. HO-3867 down-regulates FASN and FAK protein expression leading to apoptosis and decreased cell migration respectively. HO-3867 also inhibits STAT3 phosphorylation which leads to apoptosis and possibly decreased cell migration.
The curcumin analog HO-3867 has recently been shown to inhibit STAT3 and down-regulate fatty acid synthase in pancreatic cancer cells leading to apoptosis via ROS . In addition in ovarian cancer models HO-3867 down-regulates FAK . The potential to inhibit STAT3, FASN and FAK with a single agent is very promising and warrants further investigation as a potential therapeutic for pancreatic cancer (Figure 1).
- Kaplan, Mark H. ‘STAT Signaling in Inflammation’. JAK-STAT 2, no. 1 (January 2013): e24198. doi:10.4161/jkst.24198.
- Corcoran, R. B., G. Contino, V. Deshpande, A. Tzatsos, C. Conrad, C. H. Benes, D. E. Levy, J. Settleman, J. A. Engelman, and N. Bardeesy. ‘STAT3 Plays a Critical Role in KRAS-Induced Pancreatic Tumorigenesis’. Cancer Research 71, no. 14 (15 July 2011): 5020–29. doi:10.1158/0008-5472.CAN-11-0908.
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- Zecchin KG, Rossato FA, Raposo HF, Melo DR, Alberici LC, Oliveira HC, Castilho RF, Coletta RD, Vercesi AE, Graner E. Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis. Lab Invest. 2011 Feb;91(2):232-40. doi:10.1038/labinvest.2010.157. Epub 2010 Aug 30. PubMed PMID: 20805790.
- Jiang, Hong, Samarth Hegde, Brett L Knolhoff, Yu Zhu, John M Herndon, Melissa A Meyer, Timothy M Nywening, et al. ‘Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy’. Nature Medicine, 4 July 2016. doi:10.1038/nm.4123. PMID: 27376576.
- Hu Y, Zhao C, Zheng H, Lu K, Shi D, Liu Z, Dai X, Zhang Y, Zhang X, Hu W, Liang G. A novel STAT3 inhibitor HO-3867 induces cell apoptosis by reactive oxygen species-dependent endoplasmic reticulum stress in human pancreatic cancer cells. Anticancer Drugs. 2017 Jan 6. doi: 10.1097/CAD.0000000000000470. PubMed PMID: 28067673.
- Selvendiran K, Ahmed S, Dayton A, Ravi Y, Kuppusamy ML, Bratasz A, Rivera BK, Kálai T, Hideg K, Kuppusamy P. HO-3867, a synthetic compound, inhibits the migration and invasion of ovarian carcinoma cells through downregulation of fatty acid synthase and focal adhesion kinase. Mol Cancer Res. 2010 Sep;8(9):1188-97. doi: 10.1158/1541-7786.MCR-10-0201. PubMed PMID: 20713491.
AM0010 is being developed by ARMO BioSciences.
PEGylation of IL-10 allows for an extended half life in the body.
IL-10 is known to induce activation of STAT3 in CD8+ T cells which leads to increased survival, proliferation and cytotoxicity towards cancer. In preclinical studies, PEGylated IL-10 induced CD8+ T cell mediated tumor rejection and synergized with cytotoxic chemotherapies .
AM0010 is currently undergoing a phase I clinical trial for patients with advanced solid tumors including pancreatic and colon cancer . Preliminary data suggested that AM0010 enhanced immune stimulation in these “immune resistant” cancers .
It is important to note that the mechanism of action of AM0010 relies upon the presence of CD8+ T cells within the tumor. Agents that promote the presence of of these cells are likely to be synergistic with AM0010.
- Mumm JB, Emmerich J, Zhang X, Chan I, Wu L, Mauze S, Blaisdell S, Basham B, Dai J, Grein J, Sheppard C, Hong K, Cutler C, Turner S, LaFace D, Kleinschek M, Judo M, Ayanoglu G, Langowski J, Gu D, Paporello B, Murphy E, Sriram V, Naravula S, Desai B, Medicherla S, Seghezzi W, McClanahan T, Cannon-Carlson S, Beebe AM, Oft M. IL-10 elicits IFNγ-dependent tumor immune surveillance. Cancer Cell. 2011 Dec 13;20(6):781-96. doi: 10.1016/j.ccr.2011.11.003. PubMed PMID: 22172723.
- A Phase 1 Study of AM0010 in Patients With Advanced Solid Tumors. NCT02009449.
- J Clin Oncol 34, 2016 (suppl; abstr 3082). Poster.
Credit: CyanoLakes. No changes were made. Creative Commons Attribution-Share Alike 4.0 International (CC-BY-SA-4.0).
Credit: Lyn Gateley. No changes were made. Creative Commons Attribution 2.0 Generic (CC BY 2.0).
Credit: John and Carolina. No changes were made. Creative Commons Attribution-ShareAlike 2.0 Generic (CC BY-SA 2.0).
Credit: Charles Haynes. No changes were made. Creative Commons Attribution-ShareAlike 2.0 Generic (CC BY-SA 2.0).
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Credit: Hans Kylberg. No changes were made. Creative Commons Attribution 2.0 Generic.
A recent case report demonstrated that adoptive T-cell transfer targeting the KRAS G12D mutation in a metastatic colorectal cancer patient induced tumour regression . This promising result showed in a clinical setting that T cells are capable of targeting and eliminating colon tumour cells expressing KRAS G12D mutant peptides complexed with major histocompatibility complex (MHC) I proteins at their cell surface. It has implications for all cancers with prevalent mutant KRAS expression. In the most common form of pancreatic cancer PDAC, KRAS is mutated in up to 90% of cases.
Two companies Targovax and GlobeImmune are developing vaccines that contain KRAS mutant peptides for patients with pancreatic cancer. These vaccines involve injection of the peptides and subsequent in vivo generation of a T-cell response against the pancreatic cancer. Targovax’s lead RAS vaccine is called TG01. The company reported that the phase I part of a Phase I/II trial of TG01 and gemcitabine for patients with resected adenocarcinoma of the pancreas  demonstrated that TG01 induced immune responses in 92% of patients. Interim survival data showed that 14 out of 15 evaluable patients were still alive after one year. Safety and tolerability were demonstrated.
GlobeImmune’s product is clinically more advanced with efficacy shown in a subset of pancreatic pancreatic cancer patients in a phase II clinical trial (see here). A companion MALDI-TOF mass spectrometry diagnostic has been developed to predict which pancreatic cancer patient are most likely to benefit from the vaccine based on their tumours protein expression profile.
As was demonstrated by GlobeImmune’s phase II trial not all pancreatic cancer patients with KRAS mutations are guaranteed to benefit. This is most likely due to pancreatic cancer’s “cold” immunoscore (see here). KRAS vaccine combination strategies with agents that improve pancreatic cancer’s immunoscore will likely increase the number patients who respond to mutant RAS vaccines.
- Tran E, Robbins PF, Lu Y-C, et al. T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med 2016;375:2255-2262. DOI: 10.1056/NEJMoa1609279.
- ClinicalTrials.gov Identifier: NCT02261714 – Antigen-specific Cancer Immunotherapy (TG01) and Gemcitabine as Adjuvant Therapy in Resected Pancreatic Cancer.
Immunoscore is a measure of the presence of activated immune cells within a tumour as defined by the Union Internationale Contre le Cancer . Immune checkpoint inhibitors are generally not effective against tumours with a low mutational burden and low (“cold”) immunoscores. By contrast tumours such as melanoma for which immune checkpoint inhibitors are highly effective have a high (“hot”) immunoscore.
Pancreatic cancer and other solid tumours have been described to have a “cold” immunoscore which correlates with the failure of immune checkpoint inhibitors to be effective . In addition a “cold” or actively immunosuppressive solid tumour microenvironment also inhibits the mechanism of action of the class of immunotherapeutics known as CAR-T which are effective for haematological cancers.
Understanding the molecular basis of the “cold” pancreatic cancer immunoscore and developing agents that can “heat-up” pancreatic cancer is essential in order to manufacture effective immunotherapeutic treatments for this disease.
- Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, Lugli A, Zlobec I, Hartmann A, Bifulco C, Nagtegaal ID, Palmqvist R, Masucci GV, Botti G, Tatangelo F, Delrio P, Maio M, Laghi L, Grizzi F, Asslaber M, D’Arrigo C, Vidal-Vanaclocha F, Zavadova E, Chouchane L, Ohashi PS, Hafezi-Bakhtiari S, Wouters BG, Roehrl M, Nguyen L, Kawakami Y, Hazama S, Okuno K, Ogino S, Gibbs P, Waring P, Sato N, Torigoe T, Itoh K, Patel PS, Shukla SN, Wang Y, Kopetz S, Sinicrope FA, Scripcariu V, Ascierto PA, Marincola FM, Fox BA, Pagès F. Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J Pathol. 2014 Jan;232(2):199-209. doi: 10.1002/path.4287. Review. PubMed PMID: 24122236.
Heat killed Mycobacterium obuense is claimed to stimulate Th1 immune response against tumours and down regulate Th2 responses . It acts as a Pathogen-Associated Molecular Pattern (PAMP) acting on γδ T-cells, granulocytes, and antigen-presenting cells (such as dendritic cells) [2, 3]. Intradermally delivered Mycobacterium obuense has recently undergone a phase II clinical trial in advanced pancreatic cancer patients demonstrating safety and showed promising signs of efficacy that need to be confirmed in a phase III clincal trial . A systemic immune activation against pancreatic cancer is promising as these tumours are difficult for the clinician to manipulate/ manually inject.
- Charles Akle Satvinder Mudan John Grange (2013). Cancer therapy, US patent US13396866 , 2013-12-31 .
- Fowler DW, Copier J, Wilson N, Dalgleish AG, Bodman-Smith MD. Mycobacteria activate γδ T-cell anti-tumour responses via cytokines from type 1 myeloid dendritic cells: a mechanism of action for cancer immunotherapy. Cancer Immunol Immunother. 2012 Apr;61(4):535-47. doi: 10.1007/s00262-011-1121-4. PubMed PMID: 22002242.
- Bazzi S, Modjtahedi H, Mudan S, Akle C, Bahr GM. Analysis of the immunomodulatory properties of two heat-killed mycobacterial preparations in a human whole blood model. Immunobiology. 2015 Dec;220(12):1293-304. doi: 10.1016/j.imbio.2015.07.015. PubMed PMID: 26253276.
- Dalgleish AG, Stebbing J, Adamson DJ, Arif SS, Bidoli P, Chang D, Cheeseman S, Diaz-Beveridge R, Fernandez-Martos C, Glynne-Jones R, Granetto C, Massuti B, McAdam K, McDermott R, Martín AJ, Papamichael D, Pazo-Cid R, Vieitez JM, Zaniboni A, Carroll KJ, Wagle S, Gaya A, Mudan SS. Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer. Br J Cancer. 2016 Sep 27;115(7):789-96. doi: 10.1038/bjc.2016.271. PubMed PMID: 27599039
Nelfinavir trade name Viracept (Pfizer) was approved by the FDA in 1997 as a human immunodeficiency virus (HIV) therapeutic. It’s anti-HIV mechanism of action is based upon inhibiting the virus’ aspartate protease . HIV protease inhibitors including Nelfinavir have been demonstrated to inhibit the Akt pathway of cancer cell lines including pancreatic and sensitise mouse tumour xenografts to radiation therapy . Nelfinavir inhibits in vivo tumor model growth and upregulates markers of ER stress, autophagy and apoptosis . Cell death mediated by autophagy and ER stress (immunogenic cell death) is associated with immune responses against cancer .
Nelfinavir has entered a number of clinical trials for pancreatic cancer with, so far, promising but statistically low power results .
Clinical Trials .gov links
NCT01068327, NCT01959672, NCT01086332, NCT02024009
EU Clinical Trials Register links
- Koltai T. Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity. Version 2. F1000Res. 2015 Jan 12 [revised 2015 Jan 1];4:9. Doi: 10.12688/f1000research.5827.2. Review. PubMed PMID: 26097685.
- Gupta AK, Cerniglia GJ, Mick R, McKenna WG, Muschel RJ. HIV protease inhibitors block Akt signaling and radiosensitize tumor cells both in vitro and in vivo. Cancer Res. 2005 Sep 15;65(18):8256-65. PubMed PMID: 16166302.
- Gills JJ, Lopiccolo J, Dennis PA. Nelfinavir, a new anti-cancer drug with pleiotropic effects and many paths to autophagy. Autophagy. 2008 Jan;4(1):107-9. PubMed PMID: 18000394.
- Hou W, Zhang Q, Yan Z, Chen R, Zeh Iii HJ, Kang R, Lotze MT, Tang D. Strange attractors: DAMPs and autophagy link tumor cell death and immunity. Cell Death Dis. 2013 Dec 12;4:e966. doi: 10.1038/cddis.2013.493. Review. PubMed PMID: 24336086.
- Wilson JM, Fokas E, Dutton SJ, Patel N, Hawkins MA, Eccles C, Chu KY, Durrant L, Abraham AG, Partridge M, Woodward M, O’Neill E, Maughan T, McKenna WG, Mukherjee S, Brunner TB. ARCII: A phase II trial of the HIV protease inhibitor Nelfinavir in combination with chemoradiation for locally advanced inoperable pancreatic cancer. Radiother Oncol. 2016 May;119(2):306-11. Doi: 10.1016/j.radonc.2016.03.021. PubMed PMID: 27117177.