The Potential of Rigosertib in RDEB-Associated Cutaneous Squamous Cell Carcinoma

Part 1: The Current Landscape of RDEB

Andrew South, PhD, University of Wisconsin-Madison, discusses the use of rigosertib among patients with recessive dystrophic epidermolysis bullosa (RDEB)-associated cutaneous squamous cell carcinoma (cSCC).

In part 1 of this interview, Dr South outlines the current landscape of RDEB and RDEB-associated cSCC, and gives an overview of rigosertib in this space.

For Part 2 of Dr South’s interview, please click here!

Transcript:

Hi, I am Andy South. I am the Oros Family Professor in Rare Skin Diseases in the Dermatology Department at the University of Wisconsin-Madison.

What is recessive dystrophic epidermolysis bullosa (RDEB) and how does it relate to cutaneous SCC?

Recessive dystrophic epidermolysis bullosa, or RDEB, is a rare familial tumor-prone disease. It's caused by biallelic loss of function mutations in the COL7A1 gene, which encodes for the body's largest collagen protein, type 7 collagen. Now, patients born with these mutations, this biallelic loss of function mutations in COL7A1, have essentially fragile epidermis, fragile skin. They blister at the slightest trauma, and blistering primarily focuses on areas of frequent mechanical traumas — such as the hands, the knees, the elbows, the shins, and so on and so forth. Individuals are obviously born with the disease and RDEB is part of a group of diseases that are characterized by fragile epithelia, but there are some 20 genes that can cause epidermolysis bullosa, so it's a member of a wide group of genetic blistering diseases or epithelial fragility diseases.

But what makes RDEB unique is that those blisters and recurrent wounds that are hard to heal, heal with fibrosis and scarring, and it's at those sites of fibrosis and scarring —so primarily the hands and the feet and the knees, the shins, the extremities— is where cutaneous squamous cell carcinoma arise. And SCC, squamous cell carcinoma of the skin, can arise as early as the first decade of life, but more commonly it's in the second and third decades of life, so late teens, early twenties, but some patients can be cancer-free until their thirties, forties, and even fifties. But the sort of median age of tumor incidences in the twenties, early thirties.

RDEB has a range of severity dependent on the mutations and there's some contribution from the environment. The severity of your blistering and scarring and wounding correlates with incidence of squamous cell carcinoma. So patients with the most severe subtype of RDEB will get cancer earlier, and about 90% of those patients will get a cancer before the age of 50. Now, unfortunately, and regardless of the severity of the disease, unfortunately a patient with RDEB if they develop a cancer 5-year survival is averaging at 2.4 years in the most recent study. Really it is a lethal complication of what is already a devastating disease. Squamous cell carcinoma of the skin is the biggest cause of death in this patient group.

What is the current landscape of treatment for RDEB?

In the past 5 years or past 3 years, there have been 3 FDA approvals for the treatment of wounds in patients with RDEB. There isn't currently a cure, but they are palliative interventions. The first one being HSV1 gene therapy, so delivery of type 7 collagen in a cream form directly to wounds. The second one is a therapy based on birch bark extracts, so triterpenes, and that again is a cream applied to wounds, or a gel that's applied to wounds, in patients, and the studies have shown improved wound healing. And then the final approval, which has only been very recent, is an ex vivo gene therapy approach where a small piece of good, normal-looking skin from a patient is taken, the keratinocytes, the outer layer of the skin, those cells are expanded in the laboratory and then retroviral type 7 collagen is introduced to those cells — so it's a replacement therapy. Retrovirus integrates into the genome, and so those cells now express type 7 collagen, COL7A1, the gene that's missing. Cells are expanded and then grafted back onto the patient in a sort of playing card-size graft. And that has very recently been approved. And so we'll wait and see the long-term efficacy of those grafts, but that's more of a permanent replacement, but of course, it's just a small patch. And so obviously covering the entire epidermis would be challenging. And this would be focused on particular areas of wound healing, such as the knees and the hands and so on and so forth.

Now, in terms of that impact on the development of squamous cell carcinoma, the hope is that if we can improve wounds, long-term wound healing, in these patients, we reduce the number of sites that a cancer might pop up in. Tumors arise in those wounded areas. It really is a familial disease of tissue damage.

Please provide an overview of rigosertib.

We should start with rigosertib as a drug, is an experimental therapeutic. It's a small molecule. It's an allosteric inhibitor, originally identified as an inhibitor of polo-like kinase 1, but subsequently was identified to have mechanism of action against PI3 kinase and other kinases, as well as being identified as a microtubial inhibitor and also an inhibitor of oncogenic RAS. So activated RAS, it competes with activated RAS to binding to RAF has been shown in some studies. But there's some controversy about its mechanism of action.

It has been used in a number of clinical trial settings, but its main indication was myelodysplastic syndrome. And it went all the way to phase 3, and then unfortunately, I believe in 2021, failed to show any benefit in patients long-term. I think the interim analysis showed really promising results, but there was an unexpected improvement of survival in the control arm, and therefore the drug didn't meet its endpoints.

We identified the drug as a polo like kinase 1 inhibitor through laboratory studies. And one of the great aspects of the drug is that it had really strong efficacy in the nanomolar range for arresting tumor cells, the squamous cell carcinoma cells, from patients with RDEB in cell cycle at G2M arrest and induction of apoptosis, but had little effect on primary normal keratinocytes. And actually the safety profile is pretty good for this molecule as well.

And so with that in vitro data, and we had some mouse studies as well, which is xenograft tumor efficacy treating systemically with the drug, we went on to open 2 clinical trials, 2 investigator led trials of the drug, one in Europe, in Austria, Salzberg, and one in the United States at Thomas Jefferson University in Philadelphia.

For Part 2 of Dr South’s interview, please click here!

Source:

Laimer M, South AP, Kitzmueller S, et al. Efficacy and safety of rigosertib in patients with recessive dystrophic epidermolysis bullosa associated advanced/metastatic cutaneous squamous cell carcinoma. Br J Detmatol. Published online: May 25, 2025. doi: 10.1093/bjd/ljaf205.