“When you have eliminated the impossible, whatever remains, however improbable, must be the truth” Sherlock Holmes The Sign of the Four (1890)
In medical oncology there are cancers, bad cancers and then there’s adrenocortical cancer.
These tumors arise in the gland that sits just above the kidney, the source of vital hormones that include adrenaline, cortisol and aldosterone. Adrenal cancers are rare but almost uniformly fatal once they have spread.
With an incidence of only 1-2 cases per million, many medical oncologists never encounter one making data on effective treatments extremely limited.
One such case came to my attention in the spring of 2015.
Case of Metastatic Adrenocortical Cancer in 26-year-old Brazil Patient
My colleague, Renata D'Alpino Peixoto, M.D., from the Hospital Sao Jose in Sao Paulo, Brazil contacted me regarding a 26-year-old woman under her care with metastatic adrenocortical cancer.
At the time of original diagnosis in January, 2015 the disease had already disseminated. Following surgery, she received intensive chemotherapy but by May of 2015 the disease was rapidly progressing with metastases growing in the lung.
Chemotherapy for this disease consisting of Mitotane & Etoposide & Adriamycin & Cisplatin (M-EAP) is toxic but not highly effective. She suffered many side effects including weight loss, hair loss, nausea and fatigue but the cancer continued to grow.
In May, 2015 with the lung masses growing, Dr. Peixoto asked if we could use our laboratory functional profiling platform (EVA-PCD) to assist.
Despite my desire to help, I had some misgivings.
Treatment options for adrenal cortical cancers are very few and she had already failed the “gold standard”.
In addition, she would need to travel to the US for surgery and it seemed unlikely that her Brazil-based insurance would cover the costs. The procedure itself would carry some risks and the likelihood of finding an effective therapy seemed slim.
Undaunted, the patient, her husband, her two sisters and her parents arrived in my office for a consultation.
Pale, gaunt and wearing a wig there sat this young patient with her family as I explained the risks, hazards and uncertainties. They were resolute. Surgery was scheduled and a portion of the lung tumor was submitted to my lab.
Her Surprising Functional Profiling Results
The results, to say the least, were unexpected.
Despite the aggressive prior therapy my laboratory assay results found her cancer to be exquisitely sensitive to Metformin.
Metformin!
The widely used diabetes drug Metformin? That simple oral pill with almost no side effects Metformin? That Metformin?
Yes, that Metformin.
I pondered the finding and then discussed it with my colleagues in Sao Paulo. I explained that the activity observed in our laboratory should be expected to result in clinical response.
Lacking good alternatives, and with little to lose, the patient began oral Metformin at two pills a day.
Response from Brazil
Two months later, on August 28th 2015, I received this e-mail. (Quoted verbatim)
“Hi dr. It´s Monique, from Brazil! Dou you remember me?! I hope so :)
How are u? I´m really fine. I´m writing to say thank you!!!! Dr. Renata said to me that told you about the results and they are really good. However, it´s just to say thank you for your brilhant work!! I´m so proud of u!!!!
Good bless u.
King regards,
Monique.
The patient had responded beautifully to a therapy that carried virtually no side effects.
How could a drug widely used for diabetes possibly work for this patient's aggressive cancer? Although the answer is a bit beyond the scope of this blog, there is a great deal to learn from this case.
Lessons Learned
First, some of the most difficult questions have simple answers.
Second, you can’t find a treatment if you do not know where to look.
Third, cancer is a disease of altered metabolism and Metformin is a metabolic drug.
Fourth, patients do not have luxury of time.
They cannot try one drug after another hoping for a good response. Finally, our capacity to test virtually any drug or combination enables us to find drugs in the test tube, no “patient experimentation” needed.
With the broad array of drugs and combinations that we can evaluate simultaneously in the laboratory we can test hypotheses and act upon them thereby saving patients weeks, months even years of trial and error.
Our hypothesis that a metabolic therapy might work was clearly borne out as our delightful young Monique approaches her 4th year in remission.
Why Metformin is a Test Candidate
Why would we even test this drug?
It is because Metformin and the related biguanides are members of a growing number of metabolic agents. They do not damage DNA, stop mitosis or target genes.
Instead, they trap cancer cells in their most vulnerable state, one of energy dependence. Metformin, after all, is a drug that influences glucose metabolism. For diabetic patients, it lowers their blood sugar but for a cancer cell it undermines their ability to make and use energy.
This case represents a sea change in our thinking about cancer and Monique's case is the subject of a peer-reviewed, published paper (Efficacy of oral metformin in a patient with metastatic adrenocortical carcinoma: Examination of mechanisms and therapeutic implications. RD Peixoto, LM Gomes, TT Sousa, DJ Racy, M Shigenaga and RA Nagourney. Rare Tumors Volume 10: 1–7, 2018)
Although Metformin is clearly not the right drug for every patient, it was certainly the right drug for this patient.
We compiled a larger series that was reported at the 2018 American Society of Clinical Oncology (ASCO) meeting held in Chicago, June of 2018.
The Future is Studying Cellular Metabolism
Using this approach, the future of cancer medicine will be brighter, as entirely new classes of drugs that inhibit cellular metabolism rather than poisoning cell growth come to the fore.
As we move beyond genomics and the contemporary academic community’s fixation on DNA we can now refocus our efforts on biochemistry and metabolism.
This will enable us to forge the next generation of cancer therapies capable of treating this disease without the toxicities and hazards of contemporary drugs and targeted agents.
These areas of investigation had their beginnings almost a century ago when researchers like Otto Warburg first recognized that cancer cells make and use energy differently.
As I said in my TEDx Talk several years ago, “The future of cancer research lies behind us” and that future is metabolic.
As always, I appreciate your thoughts and comments.
NOTE: On Dec 2, 2018 CBS Los Angeles aired a 3 minute TV segment on Monique's story. Click here to see the video.
Dr. Robert Nagourney, has been internationally recognized as a pioneer in cancer research and personalized cancer treatment for over 20 years. He is a TEDx speaker, author of the book Outliving Cancer, a practicing oncologist and triple board certified in Internal Medicine, Medical Oncology and Hematology helping cancer patients from around the world at his Nagourney Cancer Institute in Long Beach, California. For more info go to NagourneyCancerInstitute.com