Research

It has been our fashion to scour the world looking for cures for this disease. We have tended to work as lone wolves looking out for our own care. In this area we hope to share the nuggets of interest that we discover in our travels. We hope that you can find something of benefit. It may actually be the case that the cure has already been discovered but the laboratory people have not yet twigged it. FYI Penicillin was known about long before its formal discovery in 1928 by Flemming. It took a world war to get it mass produced by 1945. So in the absence of a cure we keep looking & sticking our noses in to every nook & cranny where a cure might lurk.

 


 

July 2019 - Researchers identify effective drug combination against uveal melanoma

Researchers in Moffitt Cancer Center's Donald A. Adam Melanoma and Skin Cancer Center of Excellence are working to change that. They have identified a new drug combination that is effective against metastatic uveal melanoma cells in preclinical studies. Their findings were published in Clinical Cancer Research. You can read about it more at : https://m.medicalxpress.com/news/2019-07-effective-drug-combination-uvea...

June 2019 - Uveal Melanoma: A European Network to Face the Many Challenges of a Rare Cancer

An interesting papper setting out the vision of the EUropean Rare Adult solid CAacer Network (EURACAN) in reagrds to Uveal melanoma (UM)

Abstract:
Uveal melanoma (UM) is the most frequent primary ocular cancer in adults, accounting for 5% of all melanomas. Despite effective treatments for the primary tumour, up to 50% of UM patients will develop metastasis, leading to a very poor prognosis and a median overall survival of 6 to 12 months, with no major improvements in the last 30 years. There is no standard oncological treatment available for metastatic UM patients, and BRAF/MEK and immune checkpoint inhibitors show disappointing results when compared to cutaneous melanoma (CM). Recent advances in biology, however, identified specific gene and chromosome alterations, potentially permitting an actively tailored surveillance strategy, and dedicated clinical studies. Being a rare cancer, UM patients have to overcome issues such as identifying referral centres, having access to information, and partnering with oncologists for specific management strategies and research priorities. Here, we describe how the EUropean Rare Adult solid CAacer Network (EURACAN) will help in addressing these challenges and accelerating international collaborations to enhance the development of innovative treatments in UM.

You can read the full paper [HERE]
It is a bit technical but still very interesting.

Jan 2019 - Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma

PHILADELPHIA--Doctors diagnose about 2000 adults with uveal melanoma, a cancer of the eye, every year. In half of cases, the disease metastasizes to the liver. For these patients treatment options are scarce. Researchers at the Sidney Kimmel Cancer Center (SKCC) -- Jefferson Health and the Icahn School of Medicine at Mt. Sinai found that a compound extracted from the Christmas berry primrose plant stops the cancer's growth in preliminary tests. With further testing, the discovery could lead to new therapeutic options for patients with uveal melanoma.

"I'm very optimistic," said Jeffrey Benovic, PhD, Thomas Eakins Endowed Professor of Biochemistry & Molecular Biology at Thomas Jefferson University and an Associate Director with the SKCC, who led the new work. "If the results are confirmed in animal models and eventually humans, it could offer a new way to treat metastatic uveal melanoma patients down the road," he added.

Dr. Benovic and team published their findings in the journal Molecular Cancer Research.

Uveal melanoma (UM) is the most common eye cancer in adults. The cancer forms in melanocytes, the cells that make pigment. Although the condition differs from melanoma of the skin, both cancers are lethal. Uveal melanoma accounts for about 5 percent of all melanoma cases. Surgery or radiation is the go-to treatment for patients with primary UM that has not spread to other parts of the body. But metastases occur in about half of cases. The cancer most often travels to the liver. Once the cancer has spread, patients often only have a year or so to live as no effective therapies yet exist.

The researchers tested whether a compound derived from an ornamental plant in the primrose family known as Ardisia crenata, might be able to fight the disease.

The compound, dubbed FR900359, or simply FR, was discovered 30 years ago from the plant's leaves.

FR works by blocking a particular type of G protein that sits on a cell's membrane, called Gq - an important signaling molecule. But a subset of these proteins are mutated in uveal melanoma, turning on a molecular pathway that leads to cancer growth.

Dominic Lapadula, a graduate student in Dr. Benovic's lab, grew three different types of uveal melanoma cells that have the cancer-spurring mutations in the lab. Then he treated the cells with FR.

"We didn't expect it would work because previous research suggested a related compound called YM-254890 did not inhibit the mutated forms of the proteins found in uveal melanoma," said Dominic Lapadula. "But lo and behold, FR very effectively blocked the growth of the uveal melanoma cells." When the uveal melanoma cells were treated with small amounts of FR, the cells appeared to revert from cancer cells to typical melanocytes. "FR appears to be able to help reset the cells back to their normal state," Dr. Benovic said. "Ideally that's what you want."

Higher doses of FR killed the cells, the researchers report in the new study. The results suggest the compound could be an effective drug to treat uveal melanoma one day.

This study emanated from a team effort within the Cancer Cell Biology and Signaling program in the SKCC in collaboration with Dr. Julio Aguirre-Ghiso at the Icahn School of Medicine at Mt. Sinai. Next, Dr. Benovic would like to repeat the findings in a mouse model of uveal melanoma. To do so, he'll team up with Takami Sato, MD, PhD, Director of the Metastatic Uveal Melanoma Program at Jefferson. The program is one of the only centers dedicated to both research and treatment of the disease.

"I'm hopeful FR and related compounds will reset the cancer cells in the mouse model as it did in the cells we grew in the lab," Dr. Benovic said, "getting it one step closer to testing in humans."

"This outstanding work is part of a larger effort within our Center to develop new strategies for combating uveal melanoma. As one of the few cancer centers specializing in this aggressive cancer type, Dr. Benovic and team work closely with clinical partners within SKCC to fast track discoveries into the translational setting," said Karen E. Knudsen, PhD, Enterprise Director of the Sidney Kimmel Cancer Center.

You can jump to the published article HERE

CORDIS & UM Cure 2020

CORDIS is the Community Research and Development Information Service.

It is the European Commission's primary public repository and portal to disseminate information on all EU-funded research projects and their results in the broadest sense.

The website and repository include all public information held by the Commission (project factsheets, publishable reports and deliverables), editorial content to support communication and exploitation (news, events, success stories, magazines, multilingual "results in brief" for the broader public) and comprehensive links to external sources such as open access publications and websites.

CORDIS is managed by the Publications Office of the European Union, on behalf of the European Commission's research Directorates-General and Agencies. CORDIS content dates back to the origin of the service in 1990 and the website has been online since 1994.

You can read the CORDIS page on UM Cure 2020 at : https://cordis.europa.eu/project/rcn/199739_en.html

May 2018 - Oncogenic signaling in uveal melanoma

This is an interesting paper from Australia. In it they review the complex interactions between genetic, molecular signaling, and prognostic profiles in uveal melanoma; the clinical implications of these interactions; and the latest potential targets for rational therapy. Its another very technical document but may be of interest to some of you. You can read it in full here: https://onlinelibrary.wiley.com/doi/full/10.1111/pcmr.12708

May 2018 - Outlier response to anti-PD1

Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors. We think a lot more work needs to be done with OUTLIERS who get positive responses. We are only starting to get to grips with cancer with a long way still to go.

Abstract

Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors.

You can read the full article here 

April 2018 - Treatment of uveal melanoma: where are we now? US review paper

This paper is a helicopter view of the OM landscape as of Feb 2018 using US glases. No break thru but work is on going.

ABSTRACT

Uveal melanoma, a rare subset of melanoma, is the most common primary intraocular malignancy in adults. Despite effective primary therapy, nearly 50% of patients will develop metastatic disease. Outcomes for those with metastatic disease remain dismal due to a lack of effective therapies. The unique biology and immunology of uveal melanoma necessitates the development of dedicated management and treatment approaches. Ongoing efforts seek to optimize the efficacy of targeted therapy and immunotherapy in both the adjuvant and metastatic setting. This review provides a comprehensive, updated overview of disease biology and risk stratification, the management of primary disease, options for adjuvant therapy, and the current status of treatment strategies for metastatic disease.

You can read the full paper HERE

April 2018 - Using Genomic Sequencing to Improve Management in Melanoma:

Nothing of a break thru in this paper, more working out the risk profile. My take away is "Genomic prognostication of uveal melanomas should be pursued to determine risk and the optimal intensity of surveillance intensity;" You can have a read HERE its a two pager with equal ref to cutaneous & uveal melanomas (which is a welcome recognition for the eye folks).

 

April 2018 - NIH completes in-depth genomic analysis of 33 cancer types

This a huge project - which inter alia discovered the four subsets of Ocula Melanoma. Its closing report is rather technical in nature so only read if thats your thing.

Researchers funded by the National Institutes of Health have completed a detailed genomic analysis, known as the PanCancer Atlas, on a data set of molecular and clinical information from over 10,000 tumors representing 33 types of cancer.

"This project is the culmination of more than a decade of groundbreaking work," said NIH Director Francis S. Collins, M.D., Ph.D. "This analysis provides cancer researchers with unprecedented understanding of how, where and why tumors arise in humans, enabling better informed clinical trials and future treatments."

The PanCancer Atlas, published as a collection of 29 papers across a suite of Celljournals, sums up the work accomplished by The Cancer Genome Atlas (TCGA) - a multi-institution collaboration initiated and supported by the National Human Genome Research Institute (NHGRI) and the National Cancer Institute (NCI), both part of NIH. The program, with over $300 million in total funding, involved upwards of 150 researchers at more than two dozen institutions across North America.

"TCGA was the first project of its scale to characterize - at the molecular level - cancer across a breadth of cancer types," said Carolyn Hutter, Ph.D., director of NHGRI's Division of Genome Sciences and the NHGRI team lead for TCGA. "At the project's infancy 10 years ago, it wasn't even possible, much less on such a scale, to do the types of characterization and analysis that were being proposed. It was a hugely ambitious project."

"The PanCancer Atlas effort complements the over 30 tumor-specific papers that have been published by TCGA in the last decade and expands upon earlier pan-cancer work that was published in 2013," said Jean Claude Zenklusen, Ph.D., director of the TCGA Program Office at NCI.

The project focused not only on cancer genome sequencing, but also on different types of data analyses, such as investigating gene and protein expression profiles, and associating them with clinical and imaging data.

The PanCancer Atlas is divided into three main categories, each anchored by a summary paper that recaps the core findings for the topic. The main topics include cell of origin, oncogenic processes and oncogenic pathways. Multiple companion papers report in-depth explorations of individual topics within these categories.

In the first summary paper, the authors summarize the findings from a set of analyses that used a technique called molecular clustering, which groups tumors by parameters such as genes being expressed, abnormality of chromosome numbers in tumor cells and DNA modifications. The paper's findings suggest that tumor types cluster by their possible cells of origin, a result that adds to our understanding of how tumor tissue of origin influences a cancer's features and could lead to more specific treatments for various cancer types.

The second summary paper, presents a broad view of the TCGA findings on the processes that lead to cancer development and progression. Specifically, the authors noted that the findings identified three critical oncogenic processes: mutations, both germline (inherited) and somatic (acquired); the influence of the tumor's underlying genome and epigenome on gene and protein expression; and the interplay of tumor and immune cells. These findings will help prioritize the development of new treatments and immunotherapies for a wide range of cancers.

The final summary paper, details TCGA investigations on the genomic alterations in the signaling pathways that control cell cycle progression, cell death and cell growth, revealing the similarities and differences in these processes across a range of cancers. Their findings reveal new patterns of cancer's potential vulnerabilities that will aid in the development of combination therapies and personalized medicine.

The entire collection of papers comprising the PanCancer Atlas are available through a portal on cell.com. Additionally, as the decade-long TCGA effort wraps up, there will be a three-day symposium, TCGA Legacy: Multi-Omic Studies in Cancer, in Washington, D.C., September 27-29, 2018, that will discuss the future of large-scale cancer studies, with a session focusing on the PanCancer Atlas. The meeting will feature the latest advances on the genomic architecture of cancer and showcase recent progress toward therapeutic targeting.

You can read the full srticle & links to papers from HERE

March 2018 - Targeting MDMX and PKCδ to improve current uveal melanoma therapeutic strategies

Well this is one for the scientists among you. The fact the we see people fine tuning therapy & not just the scatter gun approach is a welcome development.

Abstract

Uveal melanoma (UM) is the most frequent ocular cancer in adults, accounting for ~5% of the total melanoma incidence. Although the primary tumor is well treatable, patients frequently develop metastases for which no curative therapy exists. Highly activated protein kinase C (PKC) is a common feature of UM and has shown potential as therapeutic intervention for UM patients. Unfortunately, PKC inhibition as single treatment appears to have only limited clinical benefit. Combining PKC inhibition with activation of p53, which is rarely mutated in UM, by MDM2 inhibitors has shown promising results in vitro and in vivo. However, clinical studies have shown strong adverse effects of MDM2 inhibition. Therefore, we investigated alternative approaches to achieve similar anticancer effects, but with potentially less adverse effects. We studied the potential of targeting MDMX, an essential p53 inhibitor during embryonal development but less universally expressed in adult tissues compared with MDM2. Therefore, targeting MDMX is predicted to have less adverse effects in patients. Depletion of MDMX, like the pharmacological activation of p53, inhibits the survival of UM cells, which is enhanced in combination with PKC inhibition. Also pan-PKC inhibitors elicit adverse effects in patients. As the PKC family consists of 10 different isoforms, it could be hypothesized that targeting a single PKC isoform would have less adverse effects compared with a pan-PKC inhibitor. Here we show that specifically depleting PKCδ inhibits UM cell growth, which can be further enhanced by p53 reactivation. In conclusion, our data show that the synergistic effects of p53 activation by MDM2 inhibition and broad spectrum PKC inhibition on survival of UM cells can also largely be achieved by the presumably less toxic combination of depletion of MDMX and targeting a specific PKC isoform, PKCδ.

You can read the full paper HERE

Nov 2017 - Why zebra fish in Ocular Melanoma research

Well thats a very good qustion and for a very good answer watch this video.

  

Aug 2017 - Study shows 4 UM Chromosome aberrations

In the August 14th issue of Cancer Cell, Robertson et al. published a study resulting from a Rare Tumour Project of The Cancer Genome Atlas (TCGA) Project where a molecular taxonomy of four clinical subsets of uveal melanoma (UM) subtypes is identified. (Full title of the study: "Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma")

You can read more here
http://www.umcure2020.org/en/the-um-2020-project/news-media/groundbreaking-study-uveal-melanoma-has-just-been-published-prestigious-journal-cancer-cell

There was a rather good presentation at the Ocu Mel UK metting this year by Professor Sarah Coupland, Director of NWCR Centre, University of Liverpool

Also note in the Q&A session after where getting a second opinion is discussed.

 


 

Feb 2017 - The biology of uveal melanoma

This is a very technical paper from Italy were, theye review the current knowledge of the biology of UM and discuss recent approaches to UM treatment. You can read it in ful here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385203/  

The UM CURE 2020 Consortium 

Uveal Melanoma (UM) is a rare intraocular disease and while the primary tumour can often be treated effectively, there is currently no effective treatment for its metastases. The overall goal of the UM Cure 2020 consortium is to combine the efforts of several European Centres of Excellence in clinical ocular oncology and basic research with patient organisations to develop new therapeutic approaches to treat metastatic UM, and share this new knowledge efficiently. to get more information on this project pop over to their website http://www.umcure2020.org/en/ 

PV-10

Provectus (OTCQB: PVCT) today announced that orphan drug designation (ODD) status was granted by the U.S. Food and Drug Administration (FDA) to small molecule oncolytic immunotherapy PV-10 for the treatment of ocular melanoma (to include all melanoma disease affecting the eye and orbit). Intratumoral injection of small molecule oncolytic immunotherapy PV-10 can yield immunogenic cell death (ICD) in solid tumor cancers and stimulate tumor-specific reactivity in circulating T cells.1-4

Whats the big deal???? Well this is the first time that we here in Ireland know of that they have injected tumors in the liver with PV-10. Before it was impossible to get deep tissue injecting. Have a look at their study paper here. One point of interest is the observation of central necrosis in one particular liver tumor. This is the tumor dying from its centre out. Which is different to it dying at its edges. We think this has WAY more potential to have successful outcomes.

We will follow, track & report on this development with much interest.