Blasting Neuroblastoma

        

Dr. Alex Carlisle

        Dr. Alex Carlisle is a neuroscientist in the Department of Neurosciences at Inova Fairfax Hospital and head of the Laboratory of Neuro-Oncology at Krasnow. He is a cancer biologist who uses molecular-based approaches to identify and functionally characterize molecules involved in the progression of various cancers. On December 6^th, 2012, he presented a power point presentation to our NEUR410 course discussing his current research: Biological and Clinical Association of CXCR4 with the Development of Peripheral Neuroblastic Tumors (pNTs).

        

        Neuroblastoma is a disease where malignant (cancerous) tumors start to develop in the sympathetic nervous system and may spread to all other parts of the body. It mainly affects infants and children. The cause of this tumor is currently unknown but Dr. Carlisle explained Phox2B, a gene found in the development of sympathoadrenal cell lineage, may be an indicator of this disease.

        

Neuroblastoma is a disease
in which malignant (cancer) cells
form in nerve tissue of the
adrenal gland, neck, chest,
or spinal cord.

        Neuroblastoma is the number one cancer found in infants, accounting for approximately 10% of all pediatric cancers and 15% of cancer related deaths in children. Early detection is vital but too often when patients are first diagnosed, it has already spread. Children who are diagnosed at 1 year old or less have the best possible outcome. The severity of their diagnosis ranges from Stage I (isolated cancer) to Stage IV (metastasis). Studies have shown on rare occasion, stage IV neuroblastoma sometimes undergoes spontaneous regression without therapeutic intervention. “We don’t know why this happens”, said Carlisle. Treatments include surgery, chemotherapy, and/or radiation. Statistics show more powerful biomarkers and improved therapies are urgently needed to diagnose neuroblastoma. What role does Carlisle’s research play in all this?

        The Carlisle laboratory studies how molecules in tumor cells from patients interact to promote the aggressive behavior of neuroblastoma. This approach allows Carlisle to identify biomarkers which may aid in improving diagnosis and prognosis. The heterogeneity of this disease makes is very difficult to study but Carlisle has identified a chemokine receptor, CXCR4, whose expression is clinically correlated with advanced stages of neuroblastoma.

Types of Neuroblastoma

        The biological roles for CXCR4 include inflammation (lymphocyte homing and recruitment into inflammatory sites), neuronal development (NPC migration during embryogenesis), metastasis, HIV infection (co-receptor for HIV binding and fusion; CD4+ cells), and cancer progression. Would knocking out CXCR4 solve the problem? No, CXCR4 is necessary for normal neuronal formation and development of an organism. A genetic knockout would yield growth malformation of the dorsal root ganglia which would kill the organism.

CT image of neuroblastoma tumor

        A variety of clinical and biological parameters are used for risk-assessment and outcome prediction of neuroblastoma. Carlisle stressed the importance of identifying the stage of the cancer which greatly helps initiate proper treatments. His research showed CXCR4 protein expression was least in ganglioneuroma (benign tumor) and progressively increased as the stages worsened with the highest expression in Stage IV neuroblastoma. This suggests CXCR4 is highly involved in signaling cancer development to metastasis.

        In an attempt to draw correlations with transcription factors, Carlisle found little evidence to show there was any significance. Do CXCR4 and MYCN interact? MYCN is a gene associated with a variety of tumors, most notably neuroblastomas. I would assume an amplification of this gene would present with higher levels of CXCR4 and neuroblastomas but Carlisle’s data showed no correlation between the two.

        Despite numerous roadblocks, Carlisle was able to find a successful treatment for these cancer cells while evaluating CXCR4-mediated signaling pathways associated with neuroblastoma progression. Plerixafor blocks CXCR4 (receptors for only CXCL12) and as a result, inhibits growth and migration of cancer cell and tumor growth. It is presumed this is accomplished by preventing macrophages from being recruited to tumors.

Chemical structure of Plerixafor

        It seems there is a lot of potential in the research Carlisle and his team are doing. Their research on receptor-mediated efficacy responses to the CXCR4-selective antagonist, Plerixafor, suggested this drug treatment is effective against the number cancer found in infants. While studying neuroblastoma maturation, they have also discovered a greater number of Schwann cells yielded to less malignant tumors and better outcome. This opens a new door to study neuroblastoma’s relationship with Schwann cells. Dr. Carlisle has encourages students interested in conducting translational research in the area of Neuro-oncology to contact his laboratory.