Learning New Tricks with an Old Drug

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What if your acne medicine could also be used to effectively treat cancer? Better yet, what if that same medicine could provide significant improvement in a matter of weeks at an incredibly low cost? This may sound too good to be true, but a recent study by cancer researchers at the University of Manchester provided promising evidence that antibiotics may indeed pack a punch against various types of cancer. In a recent interview, Dr. Michael Lisanti, a lead researcher for the study, explained the inspiration for this novel approach to cancer treatment.

While having dinner one night, cancer researchers Michael Lisanti and Federica Sotgia asked their eight-year-old daughter Camilla how she would treat patients with cancer. Her answer, in an impatient attempt to move to a more interesting conversation topic, was to take on the disease with antibiotics. As a youngster who had experienced the typical sore throats that come with childhood, this was a logical suggestion. Antibiotics target parasites and bacterial infections, but Camilla was on to something when she innocently stereotyped cancer as an infectious disease.

Cancer research trends have been moving toward the study of stem cells. These are a small number of cells from each tissue in the body that generate further cell division and differentiation, providing replacements for adult cells that are short lived. Cancers possess their own stem cells that facilitate the production of bulk cells present in tumors.

Despite the research trends, drug companies are lagging behind. According to Lisanti, most drug companies manufacture pharmaceuticals that target bulk cancer cells, not their stem cells. “They’re digging in the wrong hole,” he asserts. The relapse of tumor growth after remission in many patients provides evidence for this theory. Cancer stem cells are more resistant to traditional radiation and chemotherapy treatments, though scientists don’t completely understand why. Radiation and chemotherapy may initially prevail, but the resilient stem cells fight back vehemently, producing more aggressive cancer lines.

Cancer stem cells and Camilla’s provocative response inspired Lisanti and his research team at the University of Manchester to completely rethink cancer therapy. They decided to approach cancer treatment through the perspective of commonalities between cancer stem cells rather than differences. “This goes against what people in the field were saying,” said Dr. Lisanti. “[Many believed] each cancer needs its own biomarkers and genetic mutations.” While there is merit to understanding the integral details of each cancer type, it can prove laborious and extremely costly to develop such target specific treatments.

Mitochondria, a component found in all cancer stem cells, were the link Lisanti fixed upon to tie cancer and infectious diseases together. These organelles, or membrane bound bodies, are found inside most cells and perform numerous functions. They are needed to produce chemical energy from nutrients, control cell growth and death, and provide instructions for cell specialization. But for Lisanti, the most interesting aspect of mitochondria is that they very likely evolved from bacteria that were engulfed by primitive cells millions of years ago. Consequently, mitochondria and bacteria are very similar both in structure and function.

One of the known side effects of antibiotics in medical literature is fatigue, the result of their well tolerated toxicity toward mitochondria in healthy cells. This frequently documented symptom supported Lisanti’s hypothesis that harnessing this toxic effect for a therapeutic use against the mitochondria in cancer stem cells could work. Furthermore, the differing mutations among the cancer types would not be an issue since the antibiotics would target an analogous component in all the stem cell varieties.

Lisanti also knew about a group in Italy that had promising results researching the treatment of bacterial associated cancers. Researchers at the San Raffaele Scientific Institute in Italy were successful in treating lymphomas of the eye caused by chlamydial infections using an antibiotic. Patients participating in their clinical trial experienced significant tumor shrinkage and resistance to recurrent cancer growth following the antibiotic therapy.

Lisanti chose an array of cancers to test, growing them in a lab and then harvesting their stem cells. “We tried really hard to make our research not work,” he said. In an effort to build a robust study, he selected twelve different cancer lines from eight tumor types, including those specific to the breast, prostrate, skin, and brain. To test his antibiotic theory, the tried and true antibiotics from each of five classes were used to attempt the suppression of stem cell replication and expansion. The results were significant across the board, showing a decrease in mitochondrial function with treatment from each drug.

However, doxycycline was the study’s clear winner. Doxycycline, a member of a broad spectrum group of antibiotics referred to as the tetracyclines, has enjoyed sustained success for over forty years in treating bacterial and parasitic infections. Although certain types of bacteria have developed resistance against it, doxycycline remains a strong player in the fight against strains that cause acne and many types of respiratory and sexually transmitted diseases. It is this same antibiotic that had been successful treating chlamydial related lymphoma in Italy.

The success of doxycycline in the initial cancer stem cell research provided a strong foundation for further clinical studies. The possible ramifications of its success are striking, both in terms of economics and the lack of side effects common to most cancer drugs. A three week course of doxycycline can cost as little as five dollars, making it accessible to patients around the world. Furthermore, doxycycline is already an FDA approved drug, a factor that could expedite future clinical trials.

Further research is needed to validate the treatment of cancer as an infectious disease, including the potential development of personal resistance to the antibiotic. Despite that concern, this study showed that there may be several viable antibiotic options if resistance to one arises. More extensive testing against a greater range of cancer types is warranted as well. However, the work of Lisanti’s team, thanks to the serendipitous suggestion from an eight-year-old girl, offers a potentially powerful addition to our cancer fighting arsenal.

References

• Interview with Dr. Michael Lisanti, University of Manchester, England
• “Chlamydophila Psittaci Eradication With Doxycycline As First-Line Targeted Therapy for Ocular Adnexae Lymphoma: Final Results of an International Phase II Trial” by A. Ferriri, et al. Journal of Clinical Oncology, August 20, 2012 vol. 30 no. 24 2988-2994
• “Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease.” by Lamb, R., Ozsvari, B., Lisanti, C., Tanowitz, H., Howell, A., Martinez-Outschoorn, U., Sotgia, F., & Lisanti, M. (2015). Oncotarget, 6(7), 4569-4584