cancer

Treating Solid Tumors: Combining CAR-T Cell Therapy with Probiotics

Posted on by Johanna Lee

Chimeric Antigen Recepter (CAR)-T cell therapy is a personalized immunotherapy that harnesses the patient’s own immune system to combat cancer. It is done by engineering the patient’s T cells to specifically target and attack cancer cells in their body, and it has shown great success in treating various blood cancers such as leukemia.

Treating solid tumors with CAR-T cells, however, has proved much more challenging. This is mainly because solid tumors contain a heterogeneous population of cells, expressing a variety of antigens—many of which are also expressed in healthy cells. Therefore, T cells targeting solid tumors could potentially attack healthy tissue, resulting in serious side effects. In addition, solid tumors create a hostile microenvironment that is difficult for CAR-T cells to infiltrate.

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Three Reasons You Should Test Your CRC Patients’ MSI Status

Posted on by Jordan Nutting

Oncologists, do you know your colorectal cancer patients’ MSI status?

High-frequency microsatellite instability (MSI-H) in tumors is a form of genomic instability where mismatch repair (MMR) proteins fail to properly correct errors in microsatellite regions of the genome. When a patient’s tumor tissue is determined to have MSI-H markers, it’s strongly recommended that they be further tested for Lynch syndrome, a hereditary condition that puts them and their family at a higher risk of developing colorectal and other cancers (1).

Though as many as 1 in 279 people might be carriers for the mutations associated with Lynch syndrome (2), 95% of them don’t know it (3). Furthermore, people with Lynch syndrome have an approximately 80% increased lifetime risk of developing colorectal cancer, compared to a risk of only ~4% for the general population (4, 5).  

On Lynch Syndrome Awareness Day, here are three key reasons why you should test all your colorectal cancer patients’ MSI status.

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Conversations: Nerve-Tumor Crosstalk in the Tumor Microenvironment

Posted on by Michele Arduengo
Cancer cells are characterized by features such as metabolic reprogramming and uncontrolled proliferation all of which are supported by underlying genomic instability, inflammation and the tumor microenvironment.

Cancer cells can be distinguished from normal cells by a variety of features including their ability to inappropriately activate signals for cell proliferation, evade growth suppression from contact inhibition or tumor suppressor activity, evade cell death signals, replicate DNA continually, induce angiogenesis, invade new tissues, reprogram their metabolism to provide energy for rapid proliferation, and evade immune detection (1) . Several biological processes are responsible for these features including genomic instability, inflammation, and the creation of a tumor microenvironment.

The tumor microenvironment is the network of non-malignant cells, connective tissue and blood vessels that surround and infiltrate the tumor. These surrounding “normal” cells interact with each other and the cancer cells and are important players in tumorigenesis. One cell type that is often found in the tumor microenvironment are nerve cells. In fact, cancer cells often express proteins that encourage nerve growth into the tumor microenvironment such as growth factors and axon-guidance molecules (2). Crosstalk between nerve cells and tumor cells can facilitate development of several cancer types (2) including pancreatic, head and neck, oral, prostate, and colorectal cancers.

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Finding Signs of Cancer in Dinosaur Fossils

Posted on by Sara Klink
Centrosaurus is a herbivorous Ceratopsian dinosaur that lived in Canada in the Cretaceous Period. A recent report describes the characterization of cancer in a Centrosaurus dinosaur fossil.
Centrosaurus is a herbivorous Ceratopsian dinosaur that lived in Canada in the Cretaceous Period.

Did dinosaurs get cancer? That isn’t an easy question to answer. Finding and diagnosing cancer in dinosaur fossils has proven difficult. Any soft tissue, the typical location of tumors, has degraded over the millennia. Fossilized bones millions of years old are subject to wear and tear, making it hard to distinguish bone damage from possible pathology. By using the knowledge and expertise gained from diagnosing cancer in humans, a team reported in The Lancet Oncology that they found the first known case of osteosarcoma in a lower leg bone from a horned dinosaur found in southern Alberta, Canada.

This case of bone cancer discovered in a specimen of Centrosaurus apertus found in the Canadian Dinosaur Park Formation was confirmed by examining the bone surface along with radiographic and histological analysis. The 77–75.5-million-year-old case was compared to both a normal C. apertus fibula from the Oldman formation also in southern Alberta, Canada, as well as a human fibula with an osteosarcoma.

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In Vitro Transcription and the Use of Modified Nucleotides

Posted on by Leah Cronan
In vitro transcription
RNA polymerase unwinds DNA strands for transcription.

Transcription is the production of RNA from a DNA sequence. It’s a necessary life process in most cells. Transcription performed in vitro is also a valuable technique for research applications—from gene expression studies to the development of RNA virus vaccines.

During transcription, the DNA sequence is read by RNA polymerase to produce a complimentary, antiparallel RNA strand. This RNA strand is called a primary transcript, often referred to as an RNA transcript. In vitro transcription is a convenient method for generating RNA in a controlled environment outside of a cell.

In vitro transcription offers flexibility when choosing a DNA template, with a few requirements. The template must be purified, linear, and include a double stranded promoter region. Acceptable template types are plasmids or cloning vectors, PCR products, synthetic oligos (oligonucleotides), and cDNA (complimentary DNA). 

In vitro transcription is used for production of large amounts of RNA transcripts for use in many applications including gene expression studies, RNA interference studies (RNAi), generation of guide RNA (gRNA) for use in CRISPR, creation of RNA standards for quantification of results in reverse-transcription quantitative PCR (RT-qPCR), studies of RNA structure and function, labeling of RNA probes for blotting and hybridization or for RNA:protein interaction studies, and preparation of specific cDNA libraries, just to name a few!

In vitro transcription can also be applied in general virology to study the effects of an RNA virus on a cell or an organism, and in development and production of RNA therapeutics and RNA virus vaccines. The large quantity of viral RNA produced through in vitro transcription can be used as inoculation material for viral infection studies. Viral mRNA transcripts, typically coding for a disease-specific antigen, can be quickly created through in vitro transcription, and used in the production of vaccines and therapeutics.

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

Posted on by Johanna Lee

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.

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Out-FOXOing High-Stage Neuroblastoma

Posted on by Natalie Larsen
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.

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Immunotherapy—Don’t Forget the Microbiome

Posted on by Darcia Schweitzer

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.

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Beating the Odds of Cancer: Not Just a Tall Tale

Posted on by Radhika Ganeshan

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?

Posted on by Kari Kenefick
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.

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