Neuroendocrine neoplasms or NENs are on the rise since the pandemic; typically found in the GI tract, pancreas, lungs and liver; here we summarise emerging treatments for these rare cancers.
NENs, NETs and NECs
Neuroendocrine neoplasms are rare and can be divided into two groups, Neuroendocrine Tumours (NETs), and Neuroendorine Carcinomas (NECs). Both begin in neuroendocrine cells, part of the neuroendocrine system which is found in a number of organs throughout the body.
NETs are well differentiated and have a slower growth rate than NECs. Often classified by mitotic count and the Ki67 proliferation, NETs have a highly organised structure and large numbers of secretory granules. NETs are often treated first using surgery.
NECs are poorly differentiated but high grade and more aggressive. NECs often have up to 70% non-neuroendocrine features. NECs are typically treated with chemotherapy. The Ki67 score may be >95%. NECs are most usually found in the gastro-intestinal tract (54.1%) - locarions include the stomach, large bowel, appendix, small intestine and pancreas.Approximately 25% occur in the lungs.
Galectin-3 and NECs
NECs contain high levels of Galectin-3. It is overexpressed in NEC and is associated with initiating development, increased metastasis, chemo-resistance and poor prognosis. It is also associated with increased levels of cancer stem cells, and with promoting cancer cell adhesion,invasion, angiogenesis and immune suppression by cloaking the cancer cells. Gal-3 activates Notch transcription and regulates E-cadherin, both of which and crucial to cancer progression (9). All this would make Modified Citrus Pectin an interesting natural compound since it is known to block Galectin-3. Galectin-3 has an on-off switch which is known to be activated by natural Pectins (e.g. citrus fruits, apples, berries, bananas, apricots, carrots and more).
Neuroendocrine cells are commonly in cells of the endocrine (hormone) system but occasionally in cells of the nervous system. Strictly speaking, the majority of NENs are endocrine cancers. They most often occur in the gastrointestinal tract (small intestine, rectum, colon), where they are called carcinoid tumours, and are also found in the pancreas and lung and, more rarely, other locations such as the liver. Because these cancers may arise from the endocrine cells, they may also produce hormones.
Although many (especially NETs) originally were described as benign, they are now all classified as malignant, although some are very slow growing. One major issue is that the early tumours cause hormonal issues which may build over a period of five to seven years before the patient is diagnosed with a cancer. Other symptoms can vary from bowel obstruction to diarrhoea, uncontrolled blood sugar and gastric ulcers.
Neuroendocrine cancers and pathogens
Recent research indicates a strong correllation between viruses and NENs. Human Papilloma Virus (HPV), Epstein-Barr Virus (EBV), Hepatitis B Virus (HBV) and Kaposi-sarcoma associated herpesvirus (KSHV) may be involved (10). Somewhat ironically, researchers believe oncolytic virotherapy or virus-based immunotherapy could be future treatment options!
Pathogens and yeasts such as candida have been associated with these cancers in several studies and recurrence has been linked in particular to the presence of yeasts. It is strongly advised that patients include natural compounds in their diet that can deal with pathogenic bacteria (e.g. Artemisinin, oregano oi), viruses (pau d'arco, olive leaf extract, sea kelp); and Candida (cinnamon, fennel, oregano, artemisinin).
Conventional treatments for NETs and NECs
Typical treatment starts with surgery for NETs and/or chemotherapy with drugs such as Temozolomide (1) and/or Capecitabine (2, 3). Carboplatin with Etoposide or irinotecan with Cisplatin, are combinations used for NECs.
However, the response rate is lower than other cancers treated with these drugs; and this seems to be caused by p53 gene deficiency.
Immunotherapy is also being explored with NETs (4) and particularly the simultaneous use of Ipilimumab and Nivolumab (5), although there have been reports of liver problems in CANCERactive patients. The DART trial looked at the two immunotherapies with rare cancer and included NENs. The trial of 33 people found a 26% response in high grade NENs with partial or complete tumour shrinkage in 44% of high grade NEC tumours, but no shrinkage in low grade tumours.
Part of the problem in NECs seems to be the high recurrence rate, a function of their levels of both Galectin-3 and/or Cancer Stem Cells, which no conventional chemotherapy drugs deal with. Patients might explore off-label options such as Ivermectin, or Niclosamide, if p53 deficient; and there are a number of natural compounds capable of restricting CSCs.
These two immunotherapies seem more beneficial for high grade NECs in an overview of 37 patients from the Mayo Clinic and Moffitt Cancer Centre (6). There was even a suggestion in one trial that the addition of Black Cumin Seed oil to the combined immunotherapies, produced a better result, although rebuilding the microbiome and having strong levels of vitamin D would be more in line with multiple research studies. 2024 research has shown that NET patients have a less rich and less diversified microbiome than healthy individuals - some 31 species were abundant, 17 of which were predictive of NET presence (7).Correcting and replenishing the microbiome should afford real benefits.
Targeted therapies such as Everolimus and Sunitinib are also useful according to the American Cancer Society.
A novel approach from MD Anderson uses the hormone receptors on the tumour. They use the particular hormone to drag radiation to the tumour, killing more of the NET and saving more of the surrounding healthy cells. This is called Peptide Receptor Radionuclide Therapy, or PRRT (8). It was approved by the FDA in 2018 and reduces tumours by 80%.
Trials are also about to start involving PARP inhibitors with NENs .
Go to: How to make immunotherapy work better
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References
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Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors; Clin Canc Res 2007, Mat 15; 13(10) Sara Ekeblad et al - https://pubmed.ncbi.nlm.nih.gov/17505000/#affiliation-1
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Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience; 2013; March 7. - https://pubmed.ncbi.nlm.nih.gov/23370660/
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Outcomes of Capecitabine and Temozolomide (CAPTEM) in Advanced Neuroendocrine Neoplasms (NENs); MDPI, 14 January 2020; https://www.mdpi.com/2072-6694/12/1/206/htm
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"Present and future of immunotherapy in Neuroendocrine Tumors”; Rev Endocr Metab Disord 2021 Sep;22; - https://pubmed.ncbi.nlm.nih.gov/33851319/
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Immunotherapy of Ipilimumab and Nivolumab in Patients with Advanced Neuroendocrine Tumors; Clin Canc Res; 2020 Sep 1;26(17); Oliver Klein et al; https://pubmed.ncbi.nlm.nih.gov/32532787/
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Efficacy of ipilimumab and nivolumab in patients with high-grade neuroendocrine neoplasms; T. Al-Toubah et al; ESMO Open.
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Midgut neuroendocrine tumor patients have a depleted gut microbiome with a discriminative signature; Mulders et al; Eur J Canc 2024
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Neuroendocrine tumours at MD Anderson - 9 things to know: https://www.mdanderson.org/cancerwise/neuroendocrine-tumors--9-things-to-know.h00-159379578.html
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Galectin-3 as a novel biomarker for disease diagnosis and a target for therapy (Review); Rui Dong et al; Dec 5 2017
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Virus-associated neuroendocrine cancers: Pathogenesis and current therapeutics; Juni Bonerjee et al; Pathology - Research and Practice
Volume 248, August 2023, 154720