Using Cancer to treat Diabetes? Sort of…

Vanessa Kam

Tumour.  The word immediately summons negative connotations, embedded in the general fear surrounding cancer and impounded by the Daily Mail’s endless crusade to classify everything into cancer causes or cures.

While ‘tumour’ is often used as a synonym for ‘cancer’, in science, the two are not quite the same.  ‘Tumour’ is derived from the Latin word for ‘swelling’, and originally referred to any swelling, like a pooling of fluid in inflammation.  Nowadays it is used to refer to ‘neoplasms’ which form a mass, an abnormal growth of cells appearing bigger in size.  These masses can be benign, sticking to one location and easier to treat, or malignant, invading into other tissues and spreading around the body.  Cancer, derived from the Latin word for crab, refers to the malignant tumours, which extend out from their original site like a crab’s legs from its body.


(Cancer Cells:  Image source: National Cancer Institute)

Now that it’s clear benign tumours are not cancerous, we move on to a diabetes discovery, lest getting tied down by etymology.

In a study published in October, researchers at the Icahn School of Medicine at Mount Sinai, New York, harnessed critical information from the genomes and expression patterns of insulinoma cells.

Insulinomas are rare, small, benign tumours of pancreatic beta cells.  The pancreas is a pivotal organ in regulating blood sugar, and its beta cells secrete insulin to capture excess glucose from the bloodstream for storage.

In diabetes, beta cells are either destroyed by the patient’s own immune system (type I) or cease to function, with type II diabetes seeing a reduction in working beta cell numbers, often alongside insulin resistance.  Much work has been invested into inducing beta cells from stem cells to transplant into patients with type I diabetes, effectively replacing the destroyed cells, but what about inducing beta cells to regenerate in situ?

This is notoriously difficult, in part due to the normal development of beta cells.  Beta cell proliferation occurs shortly after birth, continues for about a year, then rapidly declines in early childhood.  In adults, the increase in beta cells is virtually zero, bad news for diabetics.  Even at its highest rate, beta cell proliferation is relatively low, with about 2% of cells dividing versus up to 50% in other cell types.  With normal proliferation rates so low in later life, there’s a particularly high barrier to promoting regeneration in adult beta cells.

This is where insulinoma comes in.  In insulinomas, beta cells proliferate.  While this generates tumours which overproduce insulin, causing patients to display symptoms of low blood sugar, identifying the mechanisms by which insulinoma cells overcome division dormancy can be applied therapeutically to diabetics, re-expanding their beta cell populations.

In fact many cancers are undergoing genomic scrutiny under various projects, including the Cancer Genome Atlas and the International Cancer Genome Consortium.  But seeing as insulinoma has a low incidence rate of two in every one million people worldwide and is largely benign—only 10% is cancerous,—insulinoma slipped through the net.

Until now.  Wang and his team at Icahn conducted whole exome sequencing and RNA sequencing on 38 benign human insulinoma samples, analysing the DNA sequence for all the protein-coding genes (exons) in the cells and the transcriptome, the variable, actively expressed portion of exons in those particular cells at that specific point in time, comparing them to normal beta cells.

They found insulinomas to display mutations and differing expression of epigenetic modifying genes—genes coding for proteins which alter the expression of other genes without changing their DNA sequence—and their targets.

One such example is a new potential drug target KDM6A.  KDM6A supports the cell cycle inhibitor CDK1NC, a protein only expressed in pancreatic beta cells and prompts their inability to divide.  CDK1NC is reduced in insulinoma, and allows beta cell proliferation when turned off.

KDM6A was mutated in several insulinoma samples in this study, prompting the team to interfere with it by inhibition using both a drug and a virus.  This resulted in lower levels of CDK1NC, which will allow beta cells to re-enter the cell cycle and proliferate, exciting news for diabetes therapy.  Future work screening for molecules which inhibit KDM6A may identify drugs promoting beta cell regeneration.

In fact, this study reaffirmed the presence of targets of a novel drug another team at Mount Sinai identified.  In 2015, after screening through 100,000 compounds, only one, harmine, was found to drive human beta cell replication in culture.  This was unheard of, with all previous attempts seeing beta cells resist pushes to multiply.

Harmine is derived from the plant harmal, which due to its psychoactive properties, is used in many spiritual rituals, hung around to protect from the ‘evil eye’ in Turkey, for example.  When used to treat mice mimicking human diabetes, harmine tripled beta cell numbers and improved blood sugar control, and is now under early development for diabetes treatment.

However even with harmine, the induced proliferation rates of beta cells are modest.  With new information about beta cell replication gathered from insulinomas, more novel drug targets can be identified and promising compounds highlighted.  This goes to show that studying rare diseases like insulinoma can bring about medical advances for the masses, with beta cell regeneration therapy now an increasing reality for the millions of diabetics worldwide.

#cancer #VanessaKam

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