Targeting IL-6: How A Drug That Helped a 6-Year-Old Beat Cancer Can Save COVID-19 Patients

In 2012, a 6-year-old girl named Emily Whitehead was battling acute lymphoblastic leukemia (ALL), one of the most common cancers in children. Her cancer was stubborn. After 16 months of chemotherapy, the cancer still would not go into remission. There was nothing else the doctors could do, and she was sent home. She was expected to survive only a few more months. Her parents would not give up and enrolled her into a clinical trial of a new immunotherapy treatment called chimeric antigen receptor (CAR) T cell therapy. She was the first pediatric patient in the program.

Doctors took T cells from Emily’s blood and reprogrammed them in a lab. They essentially sent her T cells to boot camp where they are trained to find cancer cells and destroy them. The reprogrammed T cells were then injected back into her body. A week into treatment, she started getting a fever, the first sign that the treatment was working and her reprogrammed T cells were fighting the cancer. But soon, she got very sick. All of the indicators suggested that she had cytokine release syndrome (CRS)—also known as the cytokine storm. This happens when cytokines are released in response to an infection but the process cannot be turned off. The cytokines continue to attract immune cells to the infection site, causing damage to the patient’s own cells and eventually resulting in acute respiratory distress syndrome (ARDS). (Learn more about the cytokine storm in this blog.)

Emily was soon on a ventilator. Tests showed that she had extremely high levels of one particular cytokine: interleukin-6 (IL-6). Desperate to keep her alive, her doctors gave her a known drug that specifically targets IL-6. The results were dramatic. After one single dose, her fever subsided within hours, and she was taken off the ventilator. On May 2nd, 2012, she woke up from an induced coma—it was her 7th birthday. Her doctors said they have never seen a patient that sick get better that quickly.

The drug that saved her life was tocilizumab.

Continue reading “Targeting IL-6: How A Drug That Helped a 6-Year-Old Beat Cancer Can Save COVID-19 Patients”

Out-FOXOing High-Stage Neuroblastoma

Fluorescence microscopy of neuroblastoma cells.

In recent years, scientists have been hot on the trail of transcription factor FOXO3, tracing its involvement in various tumor-centric activities comprising the many trademarks of cancer, from drug resistance to metastasis to tumor angiogenesis.

FOXO3 is a member of the O sub-class of the forkhead box family of transcription factors. The forkhead box (FOX) family is characterized by a fork head DNA-binding domain (DBD), comprised of around 100 amino acids. They have also proven themselves to be a family of many hats, functioning in diverse roles ranging from metabolism, immunology, cell-cycle control, development, as well as cancer (1). The forkhead box O (FOXO) sub-class alone has demonstrated involvement in a variety of cellular outcomes, from drug resistance and longevity to apoptosis induction.

Due to its pro-apoptotic and anti-proliferative proclivity, FOXO3 has been previously identified as a tumor suppressor gene. However, more and more studies have begun to flip the narrative on FOXO3, portraying it more as a devoted henchman, due to its roles in drug and radiotherapy resistance, cell-cycle arrest and long-term maintenance of leukemia-initiating stem cells in a variety of cancer types, including breast cancer, pancreatic cancer, glioblastoma, and both acute and chronic myeloid leukemia.

Continue reading “Out-FOXOing High-Stage Neuroblastoma”

Immunotherapy—Don’t Forget the Microbiome

Bacteria make you sick. The idea that bacteria cause illness has become ingrained in modern society, made evident by every sign requiring employees to wash their hands before leaving a restroom and the frequent food recalls resulting from pathogens like E. coli. But a parallel idea has also taken hold. As microbiome research continues to reveal the important role that bacteria play in human health, we’re starting to see the ways that the microbiota of the human body may be as important as our genes or environment.

The story of how our microbiome affects our health continues to get more complex. For example, researchers are now beginning to understand that the composition of bacteria residing in your body can significantly impact the effects of therapeutic drugs. This is a new factor for optimizing drug response, compared to other considerations such as diet, interaction with other drugs, administration time and comorbidity, which have been understood much longer.

Continue reading “Immunotherapy—Don’t Forget the Microbiome”

The Randomness of Cancer

A major scientific study grabbed headlines recently, and the implications of its findings may affect many of us, if not all of us. In a paper published in Science by Cristian Tomasetti, Lu Li and Bert Vogelstein of Johns Hopkins University, the authors report that nearly two-thirds of known cancer causing mutations can be attributed to random mistakes that occur during DNA replication. In other words, the vast majority of these mutations occur in a spontaneous, uncontrollable way— it may not matter how you live your life, or what measures you take to decrease your chance of developing cancer. As the authors and the press put it, it really just comes down to luck.

gene-mutationDisturbing? For many, yes. It’s not easy to accept that one’s luck in activities such as winning the lottery may also apply to whether or not you will be touched by cancer. That is partly why this study is gaining so much attention.

As the authors explain in their publication, until now most cancer-causing mutations had been attributed to two major sources: inherited and environmental factors. But they found that a third kind of mutation, replicative (R) mutations that arise from unavoidable errors associated with DNA replication, account for 66 percent of mutations that drive cancer. Continue reading “The Randomness of Cancer”

Shooting for the Moon: Better Assays to Hit Our Cancer Research Targets

3239CA02_1AIn his address to the clinicians, researchers, and patients at the American Association for Cancer Research meeting in April, US Vice President Joe Biden, revealed that the goal of the #cancermoonshot initiative is to accomplish 10 years of cancer research in just five years, effectively doubling the pace of cancer research (1).

Treatments developed from cancer research have come a long way with dramatic differences in the experiences and prognoses for patients, just looking back over the last 25 years. How can we double the pace of cancer research? The #cancermoonshot will one, encourage data sharing among researchers, particularly data from clinical trials. Second, it seeks to increase collaboration across industry, academic and government scientists—each community being positioned to make unique contributions to the field. And third, the initiative looks to change the current grants award process that encourages scientists to keep data and results “quiet” until they can be published or protected legally as intellectual property.

Immunotherapy is an especially hot field in cancer research (2) that relies on the immune system to better fight cancer. Continue reading “Shooting for the Moon: Better Assays to Hit Our Cancer Research Targets”

Big Data. Bigger Hope.

Research Cancer diagnosis from blood dropA paper published last week in Cancer Cell describes a new method for cancer detection from a simple blood sample. So far, one limitation of this type of non-invasive “liquid biopsy” for early detection of cancer has been the inability to identify the nature of the primary tumor. This new method, based on sequencing mRNA from platelets, overcomes this limitation in spectacular fashion—providing accurate identification of the primary tumor location in 71% of the samples tested.

Human blood platelets contain small amounts of mRNA. The RNA profile of “tumor-educated” platelets changes in response to tumor growth as the platelets take up mRNA from tumor cells. In this study, the authors sequenced the platelet mRNA of various cancer patients and healthy donors, and then searched for cancer-associated expression profiles. Continue reading “Big Data. Bigger Hope.”

Beating the Odds of Cancer: Not Just a Tall Tale

elephants_webWhen it comes to combating cancer does size matter? If every cell in the body has the propensity to become cancerous, it should naturally follow that larger animals that pack greater number of body cells and that those whose cells undergo greater number of cell divisions are more likely to develop cancer. By the same logic, organisms with longer lifespans must also have a greater chance of accumulating mutations leading to cancer. Surprisingly, the risk of developing cancer is only 5% in elephants and 18% in whales whereas it is as high as 30% in humans and rodents.  The apparent lack of correlation between body mass, longevity and cancer- known as Peto’s paradox- has flummoxed scientists for several decades.1

A recent study published in Journal of the American Medical Association  by  Abegglen and colleagues has unlocked the secret weapon held by the pachyderms in fighting cancer2. While the weapon itself might not be new to cancer biologists, the stash carried by these marvelous animals is the highest recorded for any living species so far. To understand this weapon let’s revisit the coping mechanisms developed by cells to prevent cancer. When mammalian cells are exposed to cancer inducing treatments, such as UV radiation for example, a gene encoding TP53, kicks into gear making copies of the tumor suppressing protein of the same name. TP53 acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing too fast or in an uncontrolled way. It does so by either repairing any damage to the cells caused by the UV exposure or by killing off the cell by a self-destructing mechanism known as apoptosis which is akin to committing suicide.

Many mammals, including humans carry only two copies of this important gene; one copy or allele is inherited from each parent. If the TP53 gene is inactivated by mutations, the risk of developing cancer increases by several fold. A rare but lethal condition called Li-Fraumeni Syndrome marks patients who have only one working copy of TP53 with more than a 90 percent lifetime cancer risk from childhood into their adult years.  In a quest to investigate the unexplained resistance to cancer by elephants, the scientists combed through the elephant genome and stumbled upon 40 copies of genes that code for TP53. One pair was ancestral in origin, whereas the remainder appear to have diverged from the ancestral copy and were archived within the genome over the course of evolution as retrogenes. Continue reading “Beating the Odds of Cancer: Not Just a Tall Tale”

Immune Checkpoint Inhibitors: Has Cancer Met its Match?

The cover of S. Mukerjee's book, The Emporer of All Maladies: The Biology of Cancer. Used courtesy of Wikimedia and WLU.
The cover of S. Mukerjee’s book, The Emporer of All Maladies: The Biology of Cancer. Used courtesy of Wikimedia and WLU.

Dr. Drew M. Pardoll, Johns Hopkins University School of Medicine in Baltimore, in his 2012 review, “The blockade of immune checkpoints in cancer immunotherapy” published in Nature Reviews Cancer (1) writes:

“The myriad of genetic and epigenetic alterations that are characteristic of all cancers provide a diverse set of antigens that the immune system can use to distinguish tumour cells from their normal counterparts.”

Tumors have antigens, so we should be able to address/attack these antigens with our immune system, right?

Various immune mediators as therapeutic agents against cancer have entered and mostly flopped in clinical trials over the past 30 or more years. As a graduate student in the 1980s I remember IL-2 and interferon raising many hopes. More recently, drugs against chronic myeloid leukemia and CLL have shown early promise. However, so far cancer cells have mostly won against these therapies. Yet recent news points to some exciting new therapeutic agents, that over the past 15 years or so, and in and out of clinical trials, are getting a leg up in the cancer battle. These drugs are immune checkpoint inhibitors. Continue reading “Immune Checkpoint Inhibitors: Has Cancer Met its Match?”

Amino Acid Analogs as Possible Cancer Drugs

HeLa cells stained with Hoechst 33258. By TenOfAllTrades (From English wiki 1.) [Public domain], via Wikimedia Commons
Scientists look in unusual places for potential anticancer treatments. I have reviewed papers that investigated the possibility that dandelion root may harbor anticancer treatments, milk fat may moderate cancer metastasis and the effects of chemotherapy, and black raspberry extract may even prevent cancer. Sometimes, research avenues come down to an observation about what a tumor cell needs to grow and exploring the idea that molecular analogs might be a tool to block cancer growth. For the work reported in Drug Design, Development and Therapy, analogs of the amino acid glycine, specifically glyphosate and aminomethylphosphonic acid (AMPA), the degradation product of glyphosate, were used to explore this idea in cancer cell lines. Continue reading “Amino Acid Analogs as Possible Cancer Drugs”

Healthy Lifestyles: Good for You and Your Telomeres Too

DNA in a test tubeWe all know that a healthy lifestyle (diet high in whole foods and low in fat, moderate exercise, managing stress and good social support) is good for us. In fact I will go so far as to say that it isn’t even news that these things help our health and well-being.  What is news, or at least newly published, is that these changes may also have a positive effect on telomerase activity and telomere length (1). Continue reading “Healthy Lifestyles: Good for You and Your Telomeres Too”