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Posted by Chris on December 4th, 2013  ⟩  0 comments

In the universe of cancers, there are an overabundance of different types. Not just in terms of where a particular cancer tends to show up (such as ovarian cancers, prostate cancer, etc.), but in how the cancer grows or spreads. In fact, apart from the obvious broader categorization that doctors have assembled over the last century and some smaller, subcategorizations that have happened more recently, it could be argued that every single instance of cancer is as unique as the person who has it. And why wouldn’t that be the case, after all? Every individual person has a unique genetic structure, and cancers are caused by defective genes gone awry, so it stands to reason that each cancer is technically as unique as any one person’s individual DNA.

Of course, there are millions of genes that are virtually identical in everyone…the genes that make my intestines work are probably 99.99% identical to the genes that make your intestines work. That’s just good evolutionary conservation. That also explains why cancers can be categorized at all. In the larger framework of things, our bodies are not so different. The metabolic pathways in me are mostly the same as in everyone else and any single, specific gene in one person will get upregulated or downregulated by the same growth factors as the next person.

However, that uniqueness that encompasses each one of us DOES change something in the equation. It answers (without really answering at all) why treatments respond for with some and adversely for others. It explains why cancer can sometimes be annihilated fairly easily while other times relapsing over and over again.

Compounding that penchant for variety is the problematic approach to screening new therapeutic agents. Typically, new drugs are tested first on in vitro cancer cells that have been propagated extensively over decades. But these same cell lines are far removed from the malignant tumors they are derived from. The development of the soft agar assay did wonders for our ability to study cancer outside of a patient and far removed from the threat of death. However, at the same time, they have created an artificial environment which is non-similar to the complicated mass of tumors, their supportive stromal and hematopoietic cells, and their entire vasculature. This dissimilarity makes for a large drop-off rate between in vitro and in vivo trials, eats up valuable resources and takes time away from patients who need viable options.

More recently, some doctors have grown adept in a procedure called Patient-Derived Xenograft (PDX). In a PDX, a graft of the tumor is transplanted directly into a recipient host; usually an immunocompromised mouse or rat. These PDX are usually transplanted somewhere generic, such as the subcutaneously near the hind quarters of the animal and can more closely recapitulate the biological environment that the tumor required to subsist. Current PDX methods aren’t perfect though. Some cancer varieties, such as breast cancer, are resistant to the act of xenotransplantation for some reason while others, like melanoma or lung, are much easier to graft. Regardless, PDX is providing an excellent opportunity to study and screen potential therapies on a growing variety of cancers, in something very similar to their natural setting.

In late 2011, a group from the John Hopkins University School of Medicine, led by Gary Gallia, managed to successfully transplant Chordoma into athymic mice! All by itself, that was a remarkable achievement. Chordoma is an insidious type of cancer, a bone cancer, but one that only grows in the skull or spinal portions of our body. It forms from remnants of our vestigial notochord and grows slowly and is usually diagnosed only in an adult. It is currently treatable only with surgery to remove the tumor, followed with radiation therapy to deal with what was missed in the surgery. Metastasis occurs in about 20% of patients and the 10 year survival rate is only about 46% with a median survival of patients of 6-7 years.

Then, earlier this month, Gallia’s group trumped their earlier chordoma PDX with a chemotherapeutic inhibition of the chordoma-grafted mice using either erlotinib or gefitinib, two popular EGFR (Epidermal Growth Factor Receptor) inhibitors, demonstrating the efficacy of this approach for chordomas. Overall, they saw a 70-75% reduction in tumor size after nearly double the time post-PDX.

As good as PDX is for replicating cancers in vivo, ultimately it is more useful in an academic setting than a clinical one. It will never produce results fast enough to provide the magic pill that will rid a patient of their immediate cancer. But it is an important step in the research of cancer and one I believe will continue to shed light onto a dark and convoluted metabolic pathway.

Chordoma Xenograft


Siu, I. M., Ruzevick, J., Zhao, Q., Connis, N., Jiao, Y., Bettegowda, C., & Gallia, G. L. (2013). Erlotinib Inhibits Growth of a Patient-Derived Chordoma Xenograft. PloS one, 8(11), e78895.

Siu, I. M., Salmasi, V., Orr, B. A., Zhao, Q., Binder, Z. A., Tran, C., & Gallia, G. L. (2012). Establishment and characterization of a primary human chordoma xenograft model: Laboratory investigation. Journal of neurosurgery, 116(4), 801-809.

For some additional, informative reading on PDX:
Williams, S. A., Anderson, W. C., Santaguida, M. T., & Dylla, S. J. (2013). Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century. Laboratory Investigation, 93(9), 970-982.

Category Code: 88221 79101 88231

Posted by Chris on August 22nd, 2013  ⟩  0 comments

Autophagy is a very complicated process when it comes to cancer. In general, autophagy isn’t complicated at all. It is a highly conserved process in which damaged or long-lived proteins and organelles can be removed from cells. Functioning through lysosomal machinery, this process ensures cellular survival during starvation by maintaining cellular energy levels. Think of it as a waste removal/renewable energy source system; bad or unnecessary stuff gets broken down in order to sustain the rest of the cell. This happens in nearly all cells and it works wonderfully.

In cancer, however, the role of autophagy is a bit murkier. Sometimes, autophagy is working with the doctors in the suppression of tumor cells; isolating damaged organelles, allowing cell differentiation or promoting cell death of the cancerous cells. But other times, autophagy is working against the doctors; allowing stressed tumor cells to undergo dormancy and resistance to chemotherapeutic drugs. Such a dichotomy in roles can be very frustrating to the doctors and ultimately deadly to a patient if the therapy is compromised due to the lack of effective autophagy or if the cancer comes back due to effective autophagy. Knowing which cancers use autophagy for survival and which cancers are susceptible to autophagy is key to corrective treatment.

None of this is particularly new, however. The role of autophagy in cancer cells is quite known (there is a dedicated Autophagy Journal, after all). There are also a number of clinical studies on various cancer types which are looking into the use of anti-autophagy drugs in conjunction with chemotherapy drugs. Autophagy-inhibitory drugs can come in one of two types: there are the early-stage inhibitors which can target class III P13K and interfere with its membrane recruitment, and late-stage inhibitors (such as chloroquine, hydrochloroquine and monensin) which prevent the acidification of lysosomes (Yang, 2011). Below is a table of various ongoing (c. 2011) clinical trials utilizing some of these late-stage, autophagy inhibitors.

Autophagy Clinical trials

More recently, a group in South Korea headed by Cheol Hyeon Kim investigated the effect of monensin on two anticancer drugs (erlotinib and rapamycin) in the treatment of lung cancer cells. Erlotinib is an Epidermal Growth Factor Receptor (EGFR) inhibitor which binds to the ATP binding site on the EGFR, which prevents the formation of an EGFR homodimer and its ensuing signaling cascade. Autophagy pathwayRapamycin is a macrocyclic triene, antibacterial drug which also has immunosuppressant and anticancer activities. The major target of rapamycin in mammalian cells is the mTOR pathway, which is a major regulator of autophagy, and which is downstream of the P13K-AKT pathway.

Kim’s group saw an increase in apoptosis in the cells treated with both the anticancer drug as well as nanomolar concentrations of monensin, with a 40% reduction in cells compared to the control and around ~20% reduction compared to the anticancer drug alone (P <0.01). Perhaps this isn’t really that surprisingly, after all. Hydrochloroquine in conjunction with erlotinib is already in a phase 2 trials for lung cancer (see table above). But their published record further assists in the elucidation of how autophagy functions in the realm of cancer cell tumorigenesis and ultimately, that is most important thing right now.


Choi, H. S., Jeong, E. H., Lee, T. G., Kim, S. Y., Kim, H. R., & Kim, C. H. (2013). Autophagy Inhibition with Monensin Enhances Cell Cycle Arrest and Apoptosis Induced by mTOR or Epidermal Growth Factor Receptor Inhibitors in Lung Cancer Cells. Tuberculosis and Respiratory Diseases, 75(1), 9-17.

Yang, Z. J., Chee, C. E., Huang, S., & Sinicrope, F. A. (2011). The role of autophagy in cancer: therapeutic implications. Molecular cancer therapeutics, 10(9), 1533-1541.

Category Code: 88221 79101