Metformin and LFS

Could this medication for Type 2 Diabetes help prevent cancer?

What is Metformin?

Metformin is an oral medication that decreases the amount of sugar made in the liver, helps the body use sugar and recognize the insulin receptors again. First created from French Lilac in the 1920’s to help manage diabetes, Metformin was put aside when insulin was developed. Decades later, in the 50’s the French began clinical trials and Metformin eventually became widely used in Canada, the UK and in the US during the mid 90’s to treat type 2 diabetes. The exact mechanisms of Metformin aren’t understood, but as researchers learn how it works, they get a better understanding of how the body uses sugar, how cancer cells use sugar, and if this drug could help prevent tumors.

BMC Biology: Understanding the complexity of Metformin action: limiting mitochondrial respiration to improve cancer therapy

Why Metformin for Cancer?

Doctors and scientists promote eating a healthy diet and reducing sugar intake to help prevent cancer. In 2007, researchers noticed that Metformin helped selectively starve cancer cells that did not have functioning p53. When LFS mice were put on Metformin, they grew fewer tumors. In 2008, MD Anderson began clinical trials using Metformin in breast cancer treatment, and began poring over data collected from diabetics on Metformin. They found that Metformin significantly reduced the risk of pancreatic cancer in these populations, and further studies revealed that it was even more effective as treatment in combination with other chemotherapies. A pilot study using Metformin in patients with LFS showed a decrease in mitochondrial activity and growth of tumors, similar to results seen in LFS mice. This is important for many reasons. First, mice and humans are different, so it’s important to show the mouse model and human studies correlate. Next, understanding the pathways and the way that the Metformin works is important. In LFS mutated cells, Metformin selectively affects how the mitochondrion work, therefore disrupting the supply of energy to cancer cells.

Sugar, Energy, and p53?

P53 is inactivated in half of all cancers, and scientists found that p53 is active in mitochondria and energy pathways. Since sugar control is an important part of energy pathways, they began closing the loop that links Metformin to p53. Studies revealed p53 as a player in energy metabolism, not just tumor suppression. This makes sense if we think in a broader picture of how cancer works. Cancer cells are multiplying with abandon, to do so, they need extra sources of energy. What’s a great source of energy- simple carbohydrates- sugar! PET Scans make use of this concept by injecting radioactive glucose and using a CT to visualize the uptake. The theory is that cancer cells need the sugar and take it up faster than normal cells- hence lighting up on the scan and indicating a potential cancerous growth.

I have LFS. Will Metformin Prevent Tumors?

Metformin prevented tumor growth in mice with LFS in studies. Tumor growth is a multi-step process. Cancer cells are tricky and like to find their way around medicine designed to stop them. The initial results are very promising, but like any medication, Metformin may not be good for everyone. It is best to discuss the risks and benefits of taking Metformin with your medical team. They know you and your medical history the best and can help determine if Metformin might benefit your current regimen.

How is Metformin Taken?

Metformin is a pill taken daily with meals. The dosage will depend on factors such as tolerability and side effects. It can be taken in doses of 500mg up to 2000mg. Most people start with 500 mg and increase the dose until it reaches therapeutic levels, usually at 1,500-2,000 mg.

What are the Side Effects of Metformin?

The most common side effects of Metformin are nausea, stomach pain, bloating, gas and diarrhea. These effects usually are temporary but some people experience severe effects. This is one of many reasons to be in communication with a medical professional when starting this medication.

Are There Risks with Taking Metformin?

There are some risks with taking Metformin. These risks are generally rare. It can increase the risk of low blood sugars, risk of kidney or liver damage and a condition called lactic acidosis. The risk of kidney damage can be increased with certain other medications and contrast agents, so it’s really important to let all providers know if you are taking metformin. Also, over time Metformin can deplete B12 absorption, so it is important to monitor these levels if you continue to take Metformin.

Where Can I Get more Information on Metformin and LFS?

Here are some resources to learn more about Metformin and its use in cancer prevention.

Pilot Study of Metformin in LFS Patients: https://clinicaltrials.gov/ct2/show/NCT01981525

Safety and Tolerability of Metformin in LFS Patients: https://cancerres.aacrjournals.org/content/76/14_Supplement/CT156

Cell Stress in Mouse Models: http://www.cell-stress.com/wp-content/uploads/2019/03/2019A-Donnelly-Cell-Stress-Advanced-Pub.pdf

Metformin and LFS Mice: https://tp53.co.uk/2016/12/14/metformin-and-lfs-risk-reduction-in-mice/

A Diabetic Perspective on Metformin: https://diatribe.org/everything-you-always-wanted-know-about-metformin-were-afraid-ask

An LFS Patient’s Experience in the Metformin Clinical Trial: https://www.livinglfs.org/participating-in-a-study-deb-shares-her-story-and-about-her-trip-to-nih/


COTI-2 – Big Excitement surrounding a SMALL Molecule.

One of the most exciting presentations at the REACH 16 International LFS Conference was information presented on COTI-2, a novel small molecule that helps repair some mutant p53. Dr. Wayne Danter is the Co-Founder, President and CEO of Critical Outcome Technologies, Inc., an Ontario based biopharmaceutical company that works to  “be instrumental in saving thousands of lives by enabling accelerated development of new effective treatment options.” For rare communities, like ours with Li-Fraumeni Syndrome, we truly appreciate any options that could help us. There is much excitement surrounding this small molecule, not just for those with LFS who often have treatment resistant, aggressive cancers, but for the greater cancer community. This is a groundbreaking and promising approach. A few years ago, Metformin became the first chemoprevention drug studied in LFS patients and empowered many to participate in the study. COTI-2 is a small molecule that is giving people with LFS big hope and for many this hope cannot come soon enough.

 

What is COTI-2?

COTI-2 is the name of a drug that was discovered by a computer program at Critical Outcome Technologies, called CHEMSAS.  It works by refolding certain mutant p53 in a way that helps p53 work again. COTI-2 can be taken orally and does not appear to be toxic to healthy p53 or other healthy cells. It also seems to work well with some traditional chemotherapy agents like cisplatin used to treat many LFS cancers.

Critical Outcome Technologies: criticaloutcome.com About COTI-2

How Does COTI-2 WORK?

COTI-2 works on mutated p53. When the p53 protein is made(transcribed) from the incorrect directions(mutant DNA) – sometimes it creates a less functional protein p53 or sometimes the protein doesn’t work at all. Say you have the word COT. If you change the O to an A, the word is now CAT, a word that has a different meaning but still a word. If you replace O with a C, then you have CCT. Not really a word. This is part of the reason we see so many different cancers in LFS, not all mutations are the same, some are more severe than others. Not only do the mutations make different protein shapes, the p53 protein itself has many jobs.  Some people with LFS have many cancers, others have one or two and yet others never get cancer at all. If you want to learn more about mutations, check out our blog post Some p53 Mutations are Nonsense.

Why is COTI-2 Important?

COTI-2 pg2

Critical Outcome Technologies: criticaloutcome.com About COTI-2

Of course a drug that can restore p53 is important to people with germline TP53 mutations. Clinical Trials are necessary to show that drugs are safe and effective. These trials take time and participants. The idea is that if COTI-2 is both safe and effective,  it could not only be used to treat many rare LFS cancers, but also the 50% of tumors among the general population that have mutated p53. Our LFS population is very small compared to the overall cancer community and it is part of the reason why getting trial data and targeted molecules for LFS is difficult. By creating a molecule that not only helps our rare population, but a good percentage of cancer patients in general, we will see progress.

 

How has COTI-2 been Tested?

COTI-2 molecules were chosen via computer simulation. The program looked at the structure of mutated p53 then tried to find a novel molecule that would repair the p53.  COTI-2 was used to treat cancer cells lines in petri dishes,  then p53 mutations were introduced into mouse fibroblast cells and then treated with the COTI-2 and then mouse animal models. Recently humans at MDAnderson with gynecological cancers were given Coti-2 as part of a Phase 1 trial and a direct result of COTI-2 receiving orphan drug status is important for trials like these because it facilitates the development of drugs for rare diseases like LFS that affect less than 200,ooo individuals. Researchers found, not only did COTI-2 decrease the amount of mutated p53, the amount of normal p53 increased and it was tolerated very well by the participants. Even at low doses, they saw a good response.

At the conference, Dr. Danter created much excitement when he announced they were moving ahead with the next trial in 2017. Although it may still be years away from being approved, this is a really great step. This may not be a magic bullet and cure all LFS cancers, but the hope and promise of the possibility is valued dearly and appreciated in our LFS community.

Resources

http://www.criticaloutcomeblog.com/blog-posts/p53-li-fraumeni-syndrome-and-coti-2

http://www.news-medical.net/news/20130708/p53-restoration-of-function-drug-candidate-an-interview-with-Dr-Wayne-Danter-MD-FRCPC-President-and-CEO-of-Critical-Outcome-Technologies.aspx#.V2mlICTeunI.google

Clinical Trial- https://clinicaltrials.gov/ct2/show/NCT02433626

http://criticaloutcome.com/wp-content/uploads/2015/12/151205_Orphan-Drug-Application-LFS.pdf

http://www.pharmaceuticalonline.com/doc/fda-grants-orphan-drug-status-to-coti-s-ovarian-cancer-drug-coti-0001

Dr. Danter’s Presentation