Extending the Life of Glioblastoma Patients: Gene-Modified Therapy

In a recent article posted by the Fred Hutchinson Cancer Research Center, a novel therapy is shown to improve the length of survival of patients with high-risk forms of glioblastoma. After looking at the primary research article, I noticed the researchers used many of the principals associated with personalized and targeted therpies we've recently discussed in class. But first, a little background information on glioblastoma.

According to Maciej Mrugala, the study's lead neuro oncologist, "glioblastoma remains one of the most devastating cancers with a median survival of only 12-15 months" (1). The current treatment strategy is to surgically dissect the tumor if possible, and then to treat the patient with a combination of radiation and chemotherapy. While the treatments are effective at killing the tumor, the side effects are often so severe that dosages must be reduced or treatments completely suspended. This results in less effective treatment and the faster death of the patient. However, it looks as if Adair and colleagues have developed a treatment that circumvents the common problem of toxicity and suppression of blood stem cells (HSCs).

Not all tumor cells are created equal

Introduction & Background

Stefanie Jeffrey, MD (2)

Earlier in the quarter Dr. Islas taught us that three lines of evidence – biochemical, immunological, and cytogenetic – suggested tumors are monoclonal growths.  Recall in a monoclonal growth, a single cell transforms from normal to malignant and subsequently gives rise to a tumor composed of genetically identical cells.  Together, the three experiments, from different fields, provided strong support that cancer arises from a single progenitor cell gone awry.

Alternatively, a tumor can be polyclonal in origin. In this case, multiple cells transform from normal to malignant, leading to a tumor mass composed of genetically distinct sub-populations of cells. (1) (Fig. 1)

Over the weekend, I came across a study conducted by a group of Stanford scientist who have discovered that cancer cells shed by a single tumor into the bloodstream are genetically diverse.  Some cancer cells have turned on genes that make them more adept at lodging themselves in new places, aiding in their ability to metastasize to new organs (2).  Other cancer cells have an entirely different pattern of gene expression.
The senior author of the study is Stefanie Jeffrey, MD, professor of surgery and chief of surgical oncology research at the Stanford University School of Medicine.  The research was published in PLoS ONE on May 7, 2012.

Can an anxious heart lead to and worsen cancer?

Who knew an anxious heart could have a link to cancer?
Over the winter break I browsed through a book entitled, Healing Begins with the Sanctification of the Heart by Dr. Strydom, a Zimbabwean lady who got her training and qualification to be a medical doctor in South Africa. Dr. Strydom, in her insightful book discusses how anxiety and stress can be detrimental to one's health. According to her research, stages 2 & 3 of stress (contributors to prolonged stress) cause excessive production of stress hormones in the human body including ACTH- 'the fear hormone' and cortisol. Cortisol in excessive amounts kills T cells of the immune system, and when this happens T & B cells go out of balance and B cells become overactive and begin to produce excessive antibodies, this then means that the immune system no longer functions efficiently and that the individual in question becomes more susceptible to attack by bacteria and viruses. I would like to venture further and hypothesize that knowing what we previously learnt in lecture about some viruses causing cancer, I believe that anxiety can indirectly lead to cancer via the transformation of viruses and v-oncogenes which are not destroyed by the immune system. Furthermore, we know that one of the hallmarks of cancer involves evading immune system destruction(Hanahan, Weinberg), therefore, in this case, if the immune system is already down or functioning at a less than efficient level, cancer cells may just better thrive in such an environment because a weak immune system won't be able to efficiently ward off viruses and cancer cells.

'Go Ahead, Eat Me...Oh but Wait...Don't Eat Me!' said the Cancer Cell

In a 2010 article from Stanford School of Medicine, research lead by Mark Chao and Ravindra Majet details interesting insight into the machinations of cancer cells. The researchers and their team discovered that many cancer cells actually carry the wellspring of their own ruination, this is in the form of a protein, calreticulin (CRT), an 'eat me' signal on the cell surface of cancer cells that signals circulating immune cells to engulf and digest them. So how come cancer cells are not destroyed efficiently by microphages? Now this is where it starts to get interesting, get this, cancer being the genius that it is also produces separate 'don't eat' me signals in the form of CD47 proteins on cancer cell surfaces creating a process that works to counteract the 'eat me' (CRT) signals.

Previous studies by Stanford scientists involved the characterization of the function of the 'don't eat me' (CD47) protein in cancer cells, through the studies, they established that an anti body that works to block CD47 could be a powerful anti-cancer tool in cancer therapy. They were able to illustrate through their research that anti-CD47 antibodies could eliminate disease in mice transplanted with human myeloid leukemia and also heal a grand proportion of mice with human non-Hodgkins Lymphoma when combined with a second antibody. Although fascinating, the results left the researchers astonished and with a few unanswered questions. This was partly due to the fact that the researchers knew that, CD47 can be found on many cells in the body, yet those cells are unaffected by the CD47 antibody; this observation mystified them. Research also went on to show that normal cell populations do not display CRT and therefore are not expended when they are subjected to CD47 blocking- antibodies.

This research also brought up another question that resonated with me as I was reading this article. That question is whether simply blocking CD47 expression in cancer cells would be sufficient to bring on cancer cell destruction. It turns out that  blocking the CD47- 'don't eat me' cells works to kill cancer cells because cancers like leukemias, lymphomas, and many solid tumors also display CRT-the 'eat me' signal. Interestingly, the most aggressive cancers were found to be the ones producing the most CRT, raising the hope that some of the worst cancers may be the ones most vulnerable to therapies that target CD47 and CRT in particular. This observation also suggests that the immune system works hard to try and get rid of these malignant cancer cells, the high concentration of CRT cells is a testimony to this.

DNA Methylation a Promising Tumor-Specific Marker

In class we have learned that DNA can be changed covalently by the addition of methyl groups to cytosine bases. This alteration is important in shutting down tumor suppressor genes. This article, “DNA methylation in thyroid tumorigenesis” is about how three tumor suppressor genes, CASP8, RASSF1, NIS, are being silenced due to DNA methylation. The clinicians of this study try to identify if maybe methylation is an early change in thyroid tumorigenesis regardless of the cell type. Their main goal is to recognize DNA methylation and that can be used as a biomarker to identify early thyroid cancer.

Avoid an Eye Invasion!

Uveal melanoma is a cancer of the eye involving the iris, ciliary body, or choroid (collectively referred to as the uvea). It is known as melanoma (usually related to skin cancer) because it is still a cancer that arises from the melanocytes, the pigment cells that give color to the skin and the eye.  Uveal cancer cells are known to carry a so called "class 2 signature" which ranks the metastatic cells as one of the more aggressive classes of invasive cells.

Recently, doctors at the Washington University School of Medicine in St. Louis conducted studies that show that drugs known as histone deacetylase (HDAC) inhibitors alter the conformation of the aggressive form of DNA in uveal melanoma, which changes the gene expression, which makes these invasive uveal cancer cells less aggressive. HDAC inhibitors have commonly been used to treat seizures.