Please can you introduce yourself, tell us about your background in oncology, and what inspired your latest research?
Kirill Kiselyov, Ph.D: My background is basic cell research, specifically in cell physiology and ion transporter function. I became interested in this project because of the new evidence that molecules that transport metal ions in and out of lysosomes, organelles, usually thought of as centers for degrading unwanted lipid and proteins, drive resistance to cisplatin and other chemotherapeutic drugs.
The emerging understanding of lysosomal function and new drugs that modulate ion transporters that are located in the lysosomes are likely to provide new opportunities to combat resistance to chemotherapeutic drugs.
Umamaheswar Duvvuri, M.D, Ph.D: I am a translational scientist and a practicing head and neck cancer surgeon. Dr. Kiselyov and I started collaborating to better understand how and why squamous cell carcinoma of head and neck (SCCHN) resist treatment with cisplatin. The initial finding that cisplatin can be sequestered in the lysosome led us to further interrogate this ‘lesser studied’ organelle. The current data provide intriguing information to suggest that targeting the lysosome can improve the activity of cisplatin.
According to the United Kingdom’s National Health Service, there are more than 30 areas within the head and neck where cancer can develop, with squamous cell carcinoma being the most common type among them. Can you tell us more about head and neck cancers, as well as what may cause cancers in these areas to develop?
Squamous cell carcinoma of the head & neck (SCCHN) is the most common type of Head & Neck cancer. These tumors develop from the squamous mucosa of the head & neck region (oral cavity, larynx, oropharynx etc). Typically, these cancers are caused by exposure to carcinogens like tobacco and alcohol. However, some of these cancers are caused by exposure to the human papillomavirus (HPV), that often causes tumors of the oropharynx.
Can you please provide us with an insight into the diagnosis, as well as the current treatment options available for patients with head and neck cancers?
Umamaheswar Duvvuri, M.D, Ph.D: Patients with SCCHN usually present with a neck mass. Sometimes these patients will also have symptoms of pain with swallowing, difficulty swallowing or ear pain. The diagnosis is established by performing a biopsy. After establishing this diagnosis, treatment options for the patients are discussed. Treatments for this disease include, surgery, chemotherapy, or radiation.
When patients are treated with surgery, they sometimes require adjuvant therapy with radiation or chemotherapy with radiation. When patients are treated with definitive non-surgical therapy, they are usually treated with a combination of cisplatin and radiation. The main stage of chemotherapy treatment for patients with SCCHN is cisplatin. If patients cannot tolerate cisplatin due to kidney disease, they are often treated with carboplatin, which is a close relative of cisplatin.
Cisplatin is known as a very important chemotherapy drug, but tumor resistance to cisplatin is a huge problem in the treatment of some cancers. Why is it that chemotherapy often fails for patients with cancers of the head and neck?
Kirill Kiselyov, Ph.D: Chemotherapeutic drugs work by damaging cells; for example, by interfering with their DNA. Rapidly growing and dividing cancer cells are especially sensitive to this type of damage. Modern chemotherapies are very effective, but cancer cells employ multiple mechanisms to limit the effect of chemotherapeutic drugs by repairing the damage caused by the drugs or inactivating or expelling the drugs. Our data highlight one such mechanism: the ability of cancer cells to pump cisplatin into the lysosomes, where it cannot damage their DNA, followed by its expulsion from the cell.
Your research focuses on hydroxychloroquine, a drug widely used to prevent and treat malaria, as a drug to potentially combat chemotherapy-resistant head and neck cancers. Can you briefly explain how hydroxychloroquine works in its original use as an anti-malaria medication?
Kirill Kiselyov, Ph.D: The exact mechanism of action of hydroxychloroquine in the context of malaria has not yet been established. In our study, we found that hydroxychloroquine inhibits lysosomal function, which is critical for cancer cells’ resistance to cisplatin.
Research from animal models has found that as well as being useful as a therapeutic for malaria, hydroxychloroquine also inhibits pathways that drive resistance to the chemotherapy agent, cisplatin, in head and neck cancers and restores the tumor-killing effects of cisplatin. Can you explain in more detail how hydroxychloroquine may prove useful in battling chemotherapy-resistant head and neck cancers?
Kirill Kiselyov, Ph.D: The emerging data show that cancer cells learn to sequester (hide) several types of cancer drugs in lysosomes. This decreases the efficacy of cancer drugs because their targets are usually in the cytoplasm and the nucleus. Furthermore, lysosomes help cells repair the damage.
We show that head and neck cancer cells increase the production of these organelles, increase sequestration and expulsion of the drug, and increase damage repair. Hydroxychloroquine suppresses the function of the lysosomes, and with this, the ability of cancer cells to fight chemotherapeutic drugs, including cisplatin. We think that given with or preceding cisplatin treatment, hydroxychloroquine or related drugs should significantly enhance the effect of cisplatin.
Your research findings have paved the way for a clinical trial that combines cisplatin and hydroxychloroquine as a treatment of chemotherapy-resistant head and neck cancers. Can you please provide us with more information about how you would plan to conduct these trials?
Umamaheswar Duvvuri, M.D, Ph.D: These data provide a rationale to combine cisplatin and hydroxychloroquine in the context of a clinical trial. At present, we feel that hydroxychloroquine is likely to increase cisplatin bioavailability and thus improve tumor response. We plan to test this a two-stage trial design. The first stage would confirm that these drugs are safe to use together. The second stage would then test whether the use of hydroxychloroquine and cisplatin will provide improved tumor response. We are currently delineating the specific patient population for this trial.
If these clinical trials prove to be successful in humans, are you hopeful that the outlook for patients with chemotherapy-resistant head and neck cancers will improve?
Umamaheswar Duvvuri, M.D, Ph.D: We feel that these data could significantly impact the care of patients with SCCHN. In fact, we hope to be able to treat patients in an ‘up-front’ manner and reduce the number of patients who fail cisplatin-based therapy. Of course, this requires us to test our hypotheses in the context of a clinical trial. It will take some time before we can implement this in a regular clinical setting.
What are the next steps for you and your research?
Kirill Kiselyov, Ph.D: Hydroxychloroquine is an imperfect drug; fortunately, the recent few years have seen some breathtaking advances in understanding lysosomal physiology, and as a result, new targets and new drug candidates are available. We are looking forward to testing these new targets and approaches in head and neck cancers.
Where can readers find more information?
Readers can find the full study at: https://www.pnas.org/doi/full/10.1073/pnas.2100670119
About the Researchers
Kirill Kiselyov, Ph.D: I am an Associate professor at Department of Biological Sciences, University of Pittsburgh. My research focus is lysosomal physiology and ion transport.
Umamaheswar Duvvuri, M.D, Ph.D: I am a Professor of Otolaryngology at the University of Pittsburgh. I am a practicing surgeon with a special interest in minimally invasive robotic surgery to treat patients with head and neck cancer. I have served as a Fulbright Fellow during which I helped to develop robotic programs in Malaysia and Singapore. I have taught robotic surgery in several centers around the world, including the UK, Australia and South America. My research focuses on how cancers resist therapy, so we can find ways to circumvent these resistance pathways and ultimately improve the care of patients dealing with head and neck cancer.