Ocular/Uveal/Choroidal Melanoma

Pathways

Uveal melanoma: Towards a molecular understanding (requested full text 5/14/21)

"Mutations in the Gα11/Q pathway drive uveal melanoma oncogenesis, whereas mutations in the BAP1, SF3B1 or EIF1AX genes predict progression towards metastasis. Intriguingly, the composition of chromosomal anomalies of chromosome 3, 6 and 8,  shown to correlate with an adverse outcome, are distinctive in the BAP1mutSF3B1mut and EIF1AXmut uveal melanoma subtypes. Expression profiling and epigenetic studies underline this subdivision in high-, intermediate-, or low-metastatic risk subgroups and suggest a different approach in the future towards prevention and/or treatment based on the specific mutation present in the tumor of the patients. In this review we discuss the current knowledge of the underlying genetic events that lead to uveal melanoma, their implication for the disease course and prognosis, as well as the therapeutic possibilities that arise from targeting these different aberrant pathways."

https://pubmed.ncbi.nlm.nih.gov/31563544/

*I searched "isoflavones BAP1" and found the following study, the authors of which I requested the full text on 5/14/21 to get the findings. I could not find any other results on the Gα11/Q pathway or BAP1, SF3B1 or EIF1AX genes in association with isoflavones, bacteria or other suspected natural substances that would affect the pathway and/or expression of the genes.   

Soya phytonutrients act on a panel of genes implicated with BRCA1 and BRCA2 oncosuppressors in human breast cell lines

"The aim of the present study was to determine the effects of genistein (5 microg/ml) and daidzein (20 microg/ml) on transcription in three human breast cell lines (one dystrophic, MCF10a, and two malignant, MCF-7 and MDA-MB-231) after 72 h treatment. The different genes involved in the BRCA1 and BRCA2 pathways (GADD45A, BARD1, JUN, BAX, RB1, ERalpha, ERbeta, BAP1, TNFalpha, p53, p21Waf1/Cip1, p300, RAD51, pS2, Ki-67) were quantified... We observed that, in response to treatment, many of these genes were overexpressed in the breast cancer cell lines (MCF-7 and MDA-MB-231) but not in the dystrophic cell line (MCF10a)."

https://pubmed.ncbi.nlm.nih.gov/16469160/

Next, I searched "uveal melanoma terpene" and found the artesunate study below, under "treatments!" :)

I searched "uveal melanoma phytonutrient" and found this: Withaferin A, contained in the Ayurvedic herbs Acnistus arborescens, Withania somnifera and other members of Solanaceae family, was found to inhibit the proliferation of uveal melanoma cells! 

 

Natural withanolide withaferin A induces apoptosis in uveal melanoma cells by suppression of Akt and c-MET activation

Our observation indicates that WA is a potent drug that inhibits cell proliferation, shifts cell cycle arrest, and induces apoptosis in multiple UM cell lines in vitro. WA-mediated apoptosis in UM cells is partly mediated though the suppression of c-Met and Akt activation. WA significantly decreases UM tumor growth in vivo [in animal] and justifies further evaluation of this drug for the treatment of metastatic uveal melanoma.

 

Next, I searched "uveal melanoma polyphenol," which resulted this study...!

 

Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction

"In vitro experiments with multiple uveal melanoma cell lines demonstrate that resveratrol causes a decrease in cell viability [ability to live], resulting at least in part from an increase in apoptosis [programmed cell death] through a mitochondrial pathway."

Food/plant sources of resveratrol include: 

- mulberry/fig family (Moraceae)

- lily family (Liliaceae)

- legume/bean family (Leguminosae)

- knotweed/smartweed (Polygonaceae)

- pine family (Pinaceae)

- grass family (cereal grasses, bamboos and the grasses of natural grassland)

- Ranunculaceae family (over 2000 flowering plants species)

- myrtle family (including clove, eucalyptus, guava and allspice)

- Araliaceae family (woody and herbaceous plants)

- Compositae family (daisy, sunflower, other flowering plant species)

- Magnoliaceae/magnolia family

- Juglandaceae/walnut family

- Bromeliaceae/bromeliads (monocot flowering plants)

- Pandanaceae family of flowering plants native to the tropics and subtropics of the "Old World"

- Betulaceae (birch) family

- Lauraceae (laurel) family

- Gnetaceae family

- Oleaceae (olive) family

- Ericaceae (heath/heather) flowering family

- Rosaceae (rose) family

- Rhamnaceae (buckthorn) family

- Theaceae (tea) family

- Cyperaceae (cedges/grass-like) family

- Nothofagaceae (southern or silver beach) family

- Hamamelidaceae (witch hazel) family

- Myrsinaceae (myrsine) family

- Aceraceae (maple) family

- Palmae (palms)

- Annonaceae (soursop/custard apple) family

- Euphorbiaceae (spurge) family

- Iridaceae (asparagales/iris) family

- Umbelliferae (umbellifers) family, including celery, parsley, carrot)

- Dipterocarpac ("two-winged fruit") family

 

(Source: Resveratrol: a review of plant sources, synthesis, stability, modification and food application)

Treatments

 

Study - The Anti-malarial Drug Artesunate Blocks Wnt/β-catenin Pathway and Inhibits Growth, Migration and Invasion of Uveal Melanoma Cells

https://pubmed.ncbi.nlm.nih.gov/29692251/

"Treatment with artesunate significantly induced apoptosis. In addition, artesunate significantly reduced the migration and invasion of uveal melanoma cells, impaired the traits of CSCs in vitro. Conclusion: Artesunate may be a potential interest for the therapy of uveal melanoma."

Study - Artesunate in the treatment of metastatic uveal melanoma--first experiences

https://pubmed.ncbi.nlm.nih.gov/16273263/

We report on the first long-term treatment of two cancer patients with ART in combination with standard chemotherapy. These patients with metastatic uveal melanoma were treated on a compassionate-use basis, after standard chemotherapy alone was ineffective in stopping tumor growth. The therapy-regimen was well tolerated with no additional side effects other than those caused by standard chemotherapy alone. One patient experienced a temporary response after the addition of ART to Fotemustine while the disease was progressing under therapy with Fotemustine alone. The second patient first experienced a stabilization of the disease after the addition of ART to Dacarbazine, followed by objective regressions of splenic and lung metastases. This patient is still alive 47 months after first diagnosis of stage IV uveal melanoma, a situation with a median survival of 2-5 months.

Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin [artesunate] --from bench to bedside

"The anticancer activity of artesunate has also been shown in human xenograft tumors in mice. First encouraging experience in the clinical treatment of patients suffering from uveal melanoma calls for comprehensive clinical trials with artesunate for cancer treatment in the near future."

https://pubmed.ncbi.nlm.nih.gov/17354163/

Retinoic acid elicits cytostatic, cytotoxic and immunomodulatory effects on uveal melanoma cells

For the first time we investigated the effects of retinoic acid (RA) on a panel of UM cell lines and found that RA induces morphological changes compatible with differentiation [normalization of cell function], suppresses proliferation and causes apoptosis in these cells."

https://pubmed.ncbi.nlm.nih.gov/16752155/

Network-guided modeling allows tumor-type independent prediction of sensitivity to all-trans-retinoic acid

"Uveal-melanoma and low-grade glioma are top-ranking diseases as for average predicted responsiveness to ATRA."

https://pubmed.ncbi.nlm.nih.gov/27993792/

 

Study - Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study. https://www.ncbi.nlm.nih.gov/pubmed/28395880

FINDINGS: From the completed first stage and ongoing expansion stage of this trial, a total of 21 consecutive patients with metastatic uveal melanoma were enrolled between June 7, 2013, and Sept 9, 2016, and received TIL therapy. Seven (35%, 95% CI 16-59) of 20 evaluable patients had objective tumour regression. Among the responders, six patients achieved a partial response, two of which are ongoing and have not reached maximum response. One patient achieved complete response of numerous hepatic metastases, currently ongoing at 21 months post therapy. Three of the responders were refractory to previous immune checkpoint blockade. Common grade 3 or worse toxic effects were related to the lymphodepleting chemotherapy regimen and included lymphopenia, neutropenia, and thrombocytopenia (21 [100%] patients for each toxicity); anaemia (14 [67%] patients); and infection (six [29%] patients). There was one treatment-related death secondary to sepsis-induced multiorgan failure.

Study - Transarterial Chemoembolization of Liver Metastases from Uveal Melanoma Using Irinotecan-Loaded Beads: Treatment Response and Complications

https://www.ncbi.nlm.nih.gov/pubmed/25832764

Study - Early Results of Stereotactic Radiosurgery in Uveal Melanoma and Risk Factors for Radiation Retinopathy