HadaClinic Web Journal: Thalidomide & CelecoxibFpancreatic cancer

Clinical Review

 

Prevention and Treatment with Probiotics, Thalidomide, Celecoxib and Valproic Acid for Metastatic Pancreatic Duct Adenocarcinoma.

 

Linkage between microbiota, chronic inflammation, angiogenesis and cancer

 

Masato Hada, MD, Pharmacist

Hada Clinic, clinichada@cy.tnc.ne.jp

Abstract

Currently management of patients with metastatic pancreatic duct adenocarcinoma (mPDAC) is difficult from the anatomical issue such as biliary obstruction or peritoneal and extraperitoneal dissemination and also from the resistance to cytotoxic agents.

Systematic@chemotherapy is recommended for patients with PDAC. The main agents that are thought to be effective are gemcitabine, irinotecan and taxanes which are used single or in combination.@Unfortunately, most agents have failed to improve patient survival significantly.

New therapeutic strategies incorporating pathophysiology of mPDAC are much needed. Cancer is tightly linked to chronic inflammation and angiogenesis. Chronic pancreatitis associates with PDAC, and rate for development of the cancer is 14-18 fold 1.

Angiogenesis is pathophysiological bridge between inflammation and cancer 2. Pancreatic angiogenesis occurs during the interactions between angiogenic endothelial cells and the other components of the stroma - fibroblasts, pericytes and extracellular matrix 3. Therapeutic development of antiangiogenic agents for the treatment of cancer should be aimed to block multiple angiogenic signaling pathways and their interactive loops.

However, the combination with antiangiogenic agents is not associated with treatment benefits. The cause of this failure is the choice of the agents that act on receptors and signaling pathways, not on transcriptional factors or chromatin.

Here we review the treatment of PDAC with thalidomide, celecoxib, valproic acid that act on transcriptional factors or their downstream signaling molecules.

 

Key Words : pancreatic duct adenocarcinoma(PDAC), thalidomide, celecoxib, valproic acid, transcriptional factors

 

Introduction

Microbes reside in human body, mainly on the external and internal surfaces, including the gastrointestinal tract, skin, and oral mucosa. The amount of microorganism is about  1.0-1.8kg, 1.0- 3.8 ~ 1013  in number, 1000species 4. Microorganism that provide health benefits is defined as probiotics that stimulate activity of beneficial bacteria with prebiotics such as non-digestible fibers contained in whole grain, nuts, fruits, and vegetable 5. Inflammation, especially chronic inflammation, is relevant to carcinogenesis in any malignancies. PDAC is also relevant to chronic inflammation. Patients with hereditary autoimmune pancreatitis and chronic pancreatitis have high risk for development of PDAC 6.

Pathogenesis of pancreatic inflammation is relevant to inflammatory components derived from tumor microbiome. Inflammatory components that cause pancreatitis are IL-1 receptor, caspase -1, and TNF-ƒฟ and reactive oxygen species which are able to be controlled by the currently approved drugs and probiotics 7. Emerging data have demonstrated that mutations in the KRAS gene are high in PDCA and KRAS transmits external signals to the cell nucleus. Thereafter its signals activate or irregulate transcriptional factor and promote proliferation, anti-apoptosis, angiogenesis, survival and metastasis 8. However, which transcriptional factor works for proliferation of PDCA is not demonstrated. Misunderstanding of last stage signal transduction makes the selection of chemotherapeutic agents mistaken and the chemotherapy of PDCA ineffective 9.

Tumor progression and its spreading are profoundly influenced by the environment surrounding malignant cells. Cancer is not only a disease of uncontrolled malignant cells, but also of aberrant tissue development. This aberrant tissue is called tumor microenvironment (TME) 10. The interaction between tumor cells and TME is one of the key determinants of cancer development and progression and metastasis 11.

 

Chronic Inflammation

Procarcinogenic effects of microbiome are associated with chronic inflammation.

Endotoxin and LPS are used synonymously that constitute the outer cell membrane of Gram-negative bacteria. One of pattern recognition receptors (PRRs), the best described family, are Toll-like receptors (TLRs). After binding with pathogen associated molecular patterns (PAMPs) such as LPS, PRRs play a key role in the innate immune response. TLR4 and TLR7 are highly expressed within the tumor microenvironment of PDAC and TRLs promote pancreatitis 12. LPS binds to lipid A unit of TLR4 and triggers proinflammatory processes through intracellular Toll-interleukin-1 receptor (TIR) domains. Myeloid differentiation primary response gene 88 (MyD88), one of the five TIR domain-containing adaptor proteins 13, activates transcription factors AP-1 14 , interferon regulatory factor (IRF)-5 and NF-ƒศB that promote the expression of proinflammatory interleukins including TNF-ƒฟ, IFN-ƒม, IL-1, IL-6 through the MyD88-dependent pathway 15.

 

Tumor Microenvironment and Angiogenesis

Tumor cells and surrounding microenvironment are in intimate touch constantly. More than a dozen of different proteins promote tumor angiogenesis which is pivotal for tumor growth and metastasis.  These proteins include vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor (TGF)-ƒฟ, TGF-ƒภ, tumor necrosis factor (TNF)-ƒฟ, platelet-derived growth factor (PDGF), epidermal growth factor (EGF) 16 and cyclooxygenase-2 (COX-2) 17. VEGF, bFGF and COX-2 are three key mediators of angiogenesis 18. Therapeutic development of antiangiogenic agents for the treatment of cancer should be aimed to block multiple angiogenic signaling pathways and their interactive loops 19 20 21. Until recently, the effects of the surrounding stromal tissue have been largely ignored 22. However, we began the cancer chemotherapy accepting the thought of TME since 2000.  We selected thalidomide and celecoxib that potently block VEGF, bFGF, PDGF, EGF and COX-2 in these pathways and loops of the cell 23 24 25. Pathophysiological chemotherapy with few adverse events should be recommended after first-line and second-line therapy based on the 2016 ASCO guidelines 26, or as first-line treatment for PDAC,

Chemotherapy Resistance

Continuing cancer chemotherapy, we experience chemotherapy resistance which arises from tumor related factors in tumor microenvironment.

Melanomas with BRAF V600E mutation show a response to RAF inhibitors, however responses are always partial, and recurrence occurs within 6 months 13 27.

Anticancer drug resistance is supposed to be associated with fibroblasts that secrete or do not secrete hepatocyte growth factor (HGF) and suggested a microbe may be the mediator of resistance 28. Each of probiotics 29, prebiotics, synbiotics, postbiotics, and antibiotics is one of emerging strategies for treating cancers and attenuating tumor resistance to chemotherapeutics .

The interplay between chemotherapy, immunotherapy, and microbiota could modulate chemotherapy efficacy 5. Gemcitabine is commonly used to treat PDAC, and   bacteria, mainly Gammaproteobacteria metabolize the drug into inactive form, which can be invalidated with the antibiotic ciprofloxacin. Whether bacteria are involved in tumor pathogenesis or not, they may play a critical role in resistance to chemotherapy28.

It may be important to begin the chemotherapy with probiotics and prebiotics, and when the efficay is exacerbated antibiotics like ciprofloxacin should be used.

 

Pathophysiology and Treatment

PDAC is a dismal disease. The collective median survival time for all patients is 4-6 months and the overall 5-year survival rate is 7%. About half (52%) of patients are diagnosed at stage IV, for which 5-year survival is 3% 30.

The most frequent metastatic sites of mPDAC are liver, peritoneum, lung, abdominal lymph nodes, and bones 31. Metastases to liver and lymph nodes around biliary ducts induce jaundice, peritoneal dissemination induces ascites, lymph nodes and bone metastases provoke severe pain that is difficult to control even with strong opioids. Lung metastases cause dyspnea and right pleural effusion. @

 

Liver Metastases

The dominant metastatic site of PDAC is liver (85%)32 that is nourished by both the arterial and portal venous systems. Liver metastases are a major cause of death. Premetastatic niche in the liver is a liver microenvironment permissive to render cancer cell entry through the growth factors from the primary tumor 33.

Pancreatic cancer exosomes initiate premetastatic niche formation in the liver. TGF-ƒภ secretion and upregulation of fibronectin production are caused by uptake of exosomes by Kupffer cells. In this course macrophage migration inhibitory factor (MIF) is highly expressed in exosomes 34. MIF is a pleiotropic cytokine and present in the tissue of healthy subjects. MIF is upregulated in cancers and exhibits tumor promoting properties and regulates the liver microenvironment to prepare favorable conditions for future metastasis 35. MIF also plays a key role in angiogenesis, upregulating hypoxia-inducible factor 1-alpha (HIF-1ƒฟ), VEGF, matrix metalloproteinases (MMPs) TNF-ƒฟ, prostaglandin E2 and others. Liver microenvironment consists of these protein factors and cells of the immune system 36. Overexpression of EGFR plays important roles in metastasis, especially liver metastasis and malignant transformation of PDAC37.

Thalidomide and celecoxib potently block VEGF, bFGF, PDGF, EGF and COX-2. The combination of thalidomide, celecoxib and low dose cytotoxic agent inhibits liver metastasis and shrinks metastatic lesion by blocking these growth factors38 39 40 41.

 

Malignant@Ascites

Traditional therapies, including paracentesis, peritoneovenous shunt placement and diuretics, are successful and effective in varying degrees42. However, paracentesis cause dehydration and low albuminemia, peritonevenous shunt placement promote more accumulation of ascites by infusing VPF/VEGF.@Diuretics can only decrease the fluid of vascular system, not the extravascular fluid with high osmolarity. These therapeutic options are palliative and transient, they should not be recommended for malignant ascites.

VPF is a 34-42-kD peptide secreted by tumor cells and act on microvasculature. VPF has 10,000 - 50,000 times more potent than histamine. VPF was later confirmed to promote angiogenesis. Hence its name was changed to VEGF 43. There are more than a dozen of different proteins that promote tumor angiogenesis. Misunderstanding that antiangiogenic agents are not effective for PE and ascites has caused by changing the name VPF to VEGF. The main cause of accumulation of ascites is vascular hyperpermeability by chronic inflammation. Vascular permeability is dramatically increased in cancer mediated by chronic exposure to VPF/VEGF 44. Multifunctional cytokine, VPF/VEGF contributes to angiogenesis through multiple angiogenic signaling pathways and their interactive loops. Only VPF/VEGF induces vascular hyperpermeability. Other potent angiogenic factors apparently don't mediate vascular hyperpermeability with sufficient concentrations to induce angiogenesis 45.

In order to control malignant ascites, it is important to choose inhibitory agents like thalidomdie and celecoxib which work inside the malignant cells. For example, it is completely possible to control malignant ascites using thalidomide, celecoxib and low dose cytotoxic agent that act on transcriptional factors or their downstream factors in malignant cells25. Treatment with Intraperitoneal bevacizumab (Avastin®) did not control malignant ascites 46. And without the suppression of VPF/VEGF production from primary and metastatic lesions including the abdominal cavity, a large amount of VPF/VEGF flows into the peritoneal cavity.@@

 

Cachexia

Cachexia is frequently associated with advanced metastatic PDAC and is reduced survival and quality of life. Cachexia is multi-factorial disease 47, affecting multiple organs 48. Proinflammatory cytokines, such as TNF-ƒฟ, IL-1 and IL-6, play a prominent role in the pathogenesis of cachexia in mPDCA 47. Cancer is tightly linked to chronic inflammation and angiogenesis 49. VEGF, bFGF and COX-2 are three key mediators of angiogenesis. The combination of thalidomide and celecoxib downregulate the production of TNF-ƒฟand other proinflammatory cytokines. Moreover, the combination also inhibits angiogenesis, NF-ƒศB and COX-2, therefore it is effective in the treatment of cancer cachexia. Anti-TNF-ƒฟ antibodies such as infliximab and etanercept did not show any significant improvements in cachectic patients 47 50. Because these  antibodies don't block multiple angiogenic signaling pathways and their interactive loops.

Epigenetic agents act unspecifically upon most of tumor types through inhibition of histone deacetylases (HDACs) and DNA methyltransferases. As a HDAC inhibitor, VPA suppresses tumor growth and shows significant up-regulation of hundreds of genes belonging to multiple pathways including MAPK signaling; focal adhesion, cell cycle, apoptosis, PI3K, Wnt signaling, TGF-ƒภ signalling and ubiquitin-proteasome system (UPS). VPA is an agent that should be used in combination with molecular-targeted agents and cytotoxic agents 51 52. Epigenetic agent valproic acid (VPA) proved to show potent antitumor effect by supressing angiogenesis 53.

 

Thalidomide Toxicity

Major toxicities associated with thalidomide use include birth defects, deep venous thrombosis, peripheral neuropathy, skin rash, peripheral edema and constipation 54. Less common side effects for Japanese include somnolence, fatigue, and malaise. However, the toxicities associated with thalidomide and celecoxib include skin rash, peripheral edema, and peripheral neuropathy of distal parts of legs.

 

Prevention of birth defects

Pregnancy is contraindicated.

Women of childbearing potential must use two effective contraceptives at the same time, and for male contraception and/or barrier protection.

 

In case of metastatic or far advanced state:

(Doses of thalidomide of 200 mg/day and with celecoxib 400mg/day)

*Peripheral neuropathy

Whether continue, reduce, withhold or discontinue thalidomide, it depends on the advancement state of the cancer.

*Somnolence

Take thalidomide (total daily dose        ) at bedtime and avoid hazardous tasks. Ask the patients to continue to take total dose, asking bed rest for the improvement of the cancer.

*Constipation

Constipation results from altered gastrointestinal motility. Regulating gut microenvironment with probiotics may improve motility and secretion 55.In cases of obstipation, withhold thalidomide or add laxatives to thalidomide therapy.

 

*Skin rash

Use predonisolone (30mg/day for a week)

 

*Neutropenia           

Absolute neutrophil count (ANC) =1500/mm3 Consider a granulocyte colony stimulating factor

 

Systematic Treatments

The choice of drugs is important for effective PDAC treatment. Moreover, it is necessary to select drugs considering the pathophysiology of the disease. Cellular proliferation, migration and invasion are activated by multiple pathways with aberrant autocrine and paracrine signaling. Main signaling molecules in PDAC are hepatocyte growth factor (HGF), insulin-like growth factor I (IGF-I) and angiogenic factors. Many trials have been completed trying to target these various pathways but have been unsuccessful 56, because they choose the drugs that work on receptor or signal transduction in multiple pathways, not act on molecular targets between transcriptional factors and their downstream signaling molecules directly.

Bacterial pathogens stimulate toll-like receptors on immune cells and up regulate interleukins through NF-kB and causes chronic inflammation. Treatment with   probiotics suppresses chronic inflammation. Moreover, interleukins expressed stimulate non-malignant and malignant cells and secrete various growth factors via NF-kB. These growth factors promote angiogenesis and tumor proliferation.  NF-kB plays a pivotal role in the chemotherapeutic strategy, and it is important to suppress or regulate the aberrant NF-kB.

 

Treatment

The exciting findings in the past decade are that the gut microbiota may act as a regulator of the malignant cell resistance to cytotoxic agents. At least it is important to maintain the homeostasis of gut microbiota with probiotics, prebiotics and berberine 28.

 

Probiotics

The microorganism that exert beneficial effects in human health are known as probiotics which are defined as  live microbial feed supplements including the genus Lactobacillus and Bifidobacterium. Probiotics have been shown to have anticancer effects with prebiotics 29.

 

Prebiotics

The fermentation may lead to the increased production of short-chain fatty acids (SCFAs) including acetate, propionate, and butyrate. The potential natural products are whole grains, fruits, vegetables, and nuts. SCFAs are known as HDAC inhibitors, @especially butyrate possesses significant response and modulate cancer and immunological stability 57.

 

Berberine

Berberine is an isoquinoline alkaloid purified from Japanese herb, Phellodendron amurense (KIHADA in Japanese), for a treatment of microbial diarrhea. Berberine modulates gut microbiota and reduces significantly fasting blood glucose, triglyceride, low-density lipoprotein-cholesterol and insulin resistance through inhibition of LPS/TLR4/TNF-ƒฟ signaling in the rat liver 58. The anti-inflammatory activity of berberine is induced via AMP-activated protein kinase (AMPK) activation, NF-kB inhibition and AP-1 pathway inhibition. The inhibition of these pathways by berberine plays a critical role in inflammation and carcinogenesis resulting in down-regulating the expression of cytokines, including TNF-ƒฟ, IL-1ƒภ, IL-6, monocyte chemo-attractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and COX-2 59. Neutrophils generate antimicrobial ROS (oxidative burst) and release of proteolytic peptides. The inhibitory effect of berberine on ROS production is prominent, that is, berberine shows more profound anti-inflammatory effect via neutrophil-derived ROS 60.

 

Chemotherapy

Chemotherapy with targeted agents that act on transcriptional factors should be given with cytotoxic agents including gemcitabine, irinotecan.

 

Thalidomide

Thalidomide is an immunomodulatory agent with strong antiangiogenic properties with COX-2 inhibitor celecoxib. Thalidomide inhibits the mRNA encoding such as TNF-ƒฟ and VEGF 61. In addition, thalidomide modulates activated or irregulated NF-ƒศB, resulting in suppressing malignant cell proliferation and angiogenesis as well as invasion and metastasis 62.

 

Celecoxib

COX-2 is constitutively overexpressed in chronic inflammation including premalignant, malignant, and metastatic tumors. Chronic inflammation induced by pathogens and metabolic state such as obesity leads to express COX-2. Produced prostaglandin and proinflammatory cytokines by COX-2 cause angiogenesis with subsequent carcinogenesis, tumor proliferation and metastasis, especially through NF-ƒศB 61@63

 

Valproic acid

VPA is a short fatty acid and has been used as an anti-convulsant agent. In recent years, VPA is used as HDAC inhibitor alone or in combination with other anticancer agents   64.

The induction of cell cycle arrest and apoptosis by VPA are associated with increased expression of E-cadherin and decreased expression of VGF and MMP-9 65@66.

 

 

 

 

receptor

signal transduction

transcriptional factor

chromatin

mole-

cular target

ref

Cetuximab

EGFR

 

 

 

no definite target proved@

 

 

56

 

Erlotinib

EGFR

 

 

 

Bevacizumab

VEGFR

 

 

 

 

Axitinib

VEGFR

 

 

 

Sorafenib

VEGFR, PDGFR, c-Kit

 

 

67

everolimus

temsirolimus

PI3K/AKT/mTOR pathway

 

 

68

HGF/MET inhibitors

HGF/MET pathway

 

 

 

 

 

69

IGF-1R inhibitors

 

IGF pathway

transcription factors, such as ELK1

 

 

 

70

71

 

thalidomide

 

 

NF-kB

 

VEGF, bFGF

COX-2

72

73

41

celecoxib

 

 

NF-kB COX-2

COX-2

74

41

valproic acid

 

 

 

HDACs

 

APP

bFGF

51

53

75

cytotoxic agents

 

 

NF-kB

DNA

 

 

76

 

 

Treatment with thalidomide celecoxib, and gemcitabine

February 20, 2002

July 29, 2002

April 10, 2003

Jpn J Cancer Chemother 31(6):959-961, June, 2004@77

 

Treatment with thalidomide, celecoxib and irinotecan

June 27, 2002

Gemcitabine

Oct.19, 2002

Gemcitabine

Nov.19, 2002

Gemcitabine

Feb.25, 2003

 

irinotecan

kJpn J Cancer Chemother 31(9):1407-1410, September, 2004@78

 

 

Conclusion

Combining low dose cytotoxic agent with thalidomide, celecoxib, and valproic acid has the potential to improve efficacy and attenuate resistance to mPDCA.

Before the beginning of chemotherapy, it is important to modulate irregulated immune system caused by dysbiosis with the use of probiotics, prebiotics, and berberine.

 

Inactivation of NF-kB

There are various reviews assessing the safety and efficacy of antiangiogenic agents including monoclonal antibodies (ending mab like nivolumabCbevacizumab), and inhibitory agents(ending ib like solafenib). These agents could not block multiple angiogenic signaling pathways and their interactive loops. To date, prolongation of overall survival is not ascertained 79. It is possible to estimate that signal transduction pathways are changed and complicated in 10 or 20 years more. We have to accept that chronic inflammation is continued and maintained more than 10 years and it is impossible to ameliorate these aberrant potent signals in the malignant cells with the drugs that work on the pathways in short time. Small molecule inhibitors that work inside the malignant cells and also work between transcriptional factors and various downstream signaling molecules should be selected.

 

1. thalidomide celecoxib low dose

small molecule inhibitors that work between transcriptional factors and various downstream signaling molecules

thalidomide(200mg/day)  celecoxib(400mg/day)

 

2. Epigenetic agents

   Valproic acid (600mg/day)

 

3. Cytotoxic agents with low dose

Gemcitabine, Irinotecan,

 

4. Downregulate pro-inflammatory cytokines

Berberine 100-300mg/day p.o

 

Adverse Events

Rare but Serious Adverse Events I have experienced.

Bile leakage of external Drainage --especially PTC drainage   

Percutaneous biliary drainage (PBD) for malignant obstruction is performed. External drainage is tried for a few days to decompress the biliary system, and another attempt should be selected soon. But in case of malignant obstruction, eternal external drainage must be continued. In case of PBD, cytotoxic agents must be seriously added.

In addition to various complications of PBD, bile leakage may be caused due to cellular death of granuloma by the combination of thalidomide, celecoxib and cytotoxic agent. Bile leakage, occurring from cell death of granuloma between liver and abdominal cavity, is serious and sometimes lethal to the patients with malignant diseases.

 

Conflicts of Interest

The authors have no actual or potential conflict of interest.

 

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