Pancreatic adenocarcinoma is the most common form (85%) of pancreatic cancer. Unfortunately, pancreatic cancer is often diagnosed late as early symptoms are usually non-specific. Because of this late diagnosis the prognosis for pancreatic adenocarcinoma is poor. Five year survival for cancers diagnosed at an advanced stage (most) is less than 12%.
Pancreatic cancer is the second or third most common cause of cancer death in the USA. About 64,000 people will be diagnosed with pancreatic cancer in 2023 and 46,000 will die because of this (American Cancer Society. www.cancer.org/cancer/pancreatic-cancer). Treatment for advanced pancreatic cancer is primarily chemotherapy and radiotherapy, only ~8% of these cancers have a currently targetable mutation.
Tolerance to chemotherapy is often low because of debility and nausea and vomiting in patients who may have had abdominal surgery and may have malabsorption.
There is a high medical need for well tolerated therapy to improve survival and quality of life in patients with advanced pancreatic cancer.
There is significant in vitro and in vivo data demonstrating that delta and gamma tocotrienols are active against pancreatic cancer.
Synergy has been demonstrated with gemcitabine against pancreatic cancer.
Delta and gamma tocotrienols have been shown to cause selective apoptosis (programmed cell death) of pancreatic cancer cells while leaving normal pancreas cells unaffected in preclinical studies.
Delta tocotrienol has been shown to inhibit the metastasis of pancreatic cancer cells.
Delta tocotrienol was shown to be well tolerated and to cause apoptosis of pancreatic cancer cells but not normal pancreas cells in a Phase 1 human study.
Tocotrienols are very well tolerated.
Tocotrienols (T3)
Husain K, Centeno BA, Coppola D, Trevino J, Sebti SM, Malafa MP. delta-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis. Oncotarget. 2017;8(19):31554-67.
Activity of the the various tocootrienols against pancreatic cancer was compared to gemcitabine by Husain K. Cancer Research.2008;68(9):3826.
They determined the anti proliferative (PTT assay) and pro-apoptotic activity of alpha, beta, gamma and delta tocotrienols in immortalised normal human pancreatic ductal cells (HPDE C7), HPDE cells transformed with oncogenic Kras (C7-Kras) as well as human pancreatic cancer cell lines MiaPaCa-2 and AsPc-1.
They compared the relative effect of 4 tocotrienols on malignant transformation in MiaPaCa-2 cells and on NF-kappaB activity in these cells. They also compared the tocotrienols to gemcitabine and alpha and gamma tocopherol.
Francois R. et al. Vitamin E delta-tocotrienol sensitizes human pancreatic cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIPs. Cancer Cell Int. 2019; 19: Article 189.
Similarly, Francois et al (2019) reported that delta tocotrienol augmented tumour necrosis factor-related apoptosis-inducing ligand-(TRAIL) induced apoptosis in pancreatic cancer cells. The effects were shown by the ability of delta tocotrienol to trigger caspase-8-dependent apoptosis in pancreatic cancer cells.
They tested the ability to induce apoptosis of the tocotrienols subtypes and tocopherol subtypes. Augmented apoptosis was seen with delta, gamma and beta tocotrienols in that order but not with alpha tocotrienol nor with alpha, beta, gamma or delta tocopherols.
The studies by Husain et al (2008) and Francois et al (2019) demonstrate that both delta and gamma tocotrienols exhibit anti-neoplastic activity against pancreatic cancer in vitro, with the delta form being more active in most models than the gamma form.
In a paper published in 2011: Husain K et al. Delta tocotrienol augments the anti-tumour activity of gemcitabine and suppresses constitutive NF-kappaB activation in pancreatic cancer. Mol Cancer Ther. 2011; 10(12): 2363-2372.
Husain describes that NF-kappaB transcription factor functions as a crucial regulator of cell survival and chemo resistance in pancreatic cancer.
In a series of studies in mice Husain demonstrated:
In summary gemcitabine and delta tocotrienol significantly (p<0.001) decreased the proliferation of AsPc-1 and MiaPaCa-2 cells compared to vehicle control with the combination being more effective than either compound alone. The combination produced more cancer cell deaths than either alone. Delta tocotrienol has been demonstrated to augment gemcitabine’s anti-cancer activity both in vitro and in vivo.
Prolonged survival with delta tocotrienol and in combination with gemcitabine was demonstrated in the transgenic mouse model of pancreatic cancer. Husain K.Cancer Prev Res (Phil).2013; 6(10):1070-1083.
Transgenic mice were randomised to 4 groups:
The mice were treated until there were symptoms of impending death then euthanised.
At 16 weeks survival was:
Gamma tocotrienol was studied as an anti-tumour agent against pancreatic cancer in a series of experiments by Kunnumakkara. (Kunnumakkara A et al. gamma tocotrienol inhibits pancreatic tumours and sensitises them to gemcitabine treatment by modulating the micro inflammatory environment. Cancer Res. 2010; 70(21):8695-8705)
In his initial in vitro studies he demonstrated that gamma tocotrienol potentiated the apoptotic effect of gemcitabine in pancreatic cancer cells (AsPC-1, MIA PaCa-2, BxPC-3 and PANC-1). They used a LIVE/DEAD cell viability assay kit and incubated cells with vehicle (control), gamma tocotrienol, gemcitabine or both. The % apoptosis was much greater with the combination.
He then showed that gamma tocotrienol potentiates the effect of gemcitabine in blocking the growth of pancreatic cancer cells in orthotropic nude mice. After luciferase-transfected MIA PaCA-2 cells were implanted in the tails of mice, one week later the mice were randomised to 4 groups and administered:
Tumour control was reduced in all groups compared to control but most markedly in the combination group.
Kunnumakkara also demonstrated that gamma tocotrienol enhanced the effect of gemcitabine on expression of NF-kappaB and NF-kappaB regulated genes in pancreatic cancer (p<0.001) as well as against tumour proliferation.
The Moffitt Cancer Center in Florida conducted a Phase 1 Safety, Pharmacokinetic and Pharmacodynamic Presurgical Trial of delta tocotrienol in patients with pancreatic ductal adenocarcinoma. (Springett H et al. EBioMedicine. 2015 Dec;2:1987-95) Patients who were scheduled for surgery for their pancreatic cancer were enrolled in the study. Patients received oral delta tocotrienol at escalating doses from 200 to 3200mg daily for 13 days before surgery. Dose escalation followed a 3 + 3 trial design. The primary end points were safety, kinetics and delta tocotrienol induced apoptosis.
Twenty-five patients were enrolled, no dose limiting toxicity was observed, therefore no MTD was reached. One patient had diarrhoea at 3200mg daily. The elimination half life of delta tocotrienol was ~4 hours. Tmax was at ~5.6 hours. Plasma levels showed considerable interpatient variation but reached bioactive levels based on preclinical models. Bioactivity , defined as significant induction of apoptosis in neoplastic cells as measured by increased caspase 3 levels, was seen in the majority of patients at 400 to 1600mg daily doses. Apoptosis was seen in neoplastic and dysplastic tissue but not in nearby normal tissue.
Delta tocotrienol has been demonstrated to have anti-cancer activity against pancreatic cancer cells in both pre-clinical studies and a phase 1 human study.
The activity is selective for pancreatic cancer cells and spares normal pancreas cells.
The activity augments the anti-cancer effect of gemcitabine.
Inhibition of spread of pancreatic cancer metastases has also been shown.
Invictus’ pancreatic cancer drug candidate IVB003 uses our patented TransT3 delivery platform to deliver tocotrienols transmucosally (via sublingual and buccal absorption). View Transmucosal vs. Oral Administration.
Invictus has also observed that a direct delivery platform closely related to the TransT3 platform being used in Australian complementary medicines has shown substantial improvements in efficacy in muscle-related indications such as Delayed Onset Muscle Soreness (DOMS), muscle recovery and maintenance of muscle power compared to Australian complementary medicines which have orally administered tocotrienols.
There is a very strong case for a proof of concept study to elucidate the effect of transmucosal delta tocotrienol in pancreatic cancer.
A Multi-center, randomized, double-Blind, Efficacy and Safety Study of Sublingual Invictus Tocotrienols or Placebo added to Standard of Care (SOC) Therapy in Locally Advanced or Metastaic Pancreatic Adenocarcinoma.
The study is currently undergoing Ethics Committee approval.
“For pancreatic cancer patients, tolerance of the chemotherapy is often low because of debility and nausea and vomiting in these patients who may have had abdominal surgery and have malabsorption. Invictus’ TransT3 and TPD platforms for delivery of T3s have the potential to circumvent the issue of malabsorption of chemotherapies.”
“T3s delivered using Invictus’ TransT3 and TPD platforms have the potential to provide a specific type of opportunity in treatment of human pancreatic cancer. A growing body of evidence has shown cancer stem cells within a tumor may give rise to therapy resistance and metastasis. Recent studies have shown that T3 treatment inhibits the growth of pancreatic cancer stem cells. Assessment of Invictus’ TransT3 and T3 prodrugs impact on pancreatic cancer stem cells in preclinical studies has the potential to provide a valuable new opportunity to impact pancreatic cancer mortality.”
“The global pancreatic cancer treatment market is expected to reach USD 4.2 billion in 2025, according to a new report by Grand View Research, Inc. …growing geriatric population is also expected to drive the growth during the forecast period.”
Ref: prnewswire.com
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