Kidney Cancer: Nervous System Protein May Provide New Therapeutic Target

dr_john-coplandMedicalResearch.com Interview with:
Dr. John A. Copland, PhD
Associate Professor of Biochemistry/Molecular Biology
Professor of Cancer Biology
Cancer Basic Science
Mayo Clinic, Jacksonville, Florida

MedicalResearch: What are the main findings of the study?

Dr. Copland: In our study we identified a pro-cancerous role for a novel protein- neuronal pentraxin 2 (NPTX2). This protein, normally found expressed in brain and nervous system tissues, is highly overexpressed in kidney tumors at all stages of disease. It has never previously been associated with kidney cancer, nor has it been associated with an oncogenic function in any other cancer. NPTX2 appears to play a significant role in not only tumor cell survival, but it also promotes tumor cell migration through activation of the ionotropic glutamate receptor 4 (GluR4). GluR4, also commonly associated with nervous system tissues, appears to be manipulating the flow of calcium into the tumor cell. Both NPTX2 and GluR4 are not components of normal kidney cell function. Because calcium is an important co-factor for many signaling pathways controlling cell growth, survival, and mobility, unconstrained calcium levels in a cell can promote malignancy. We show that calcium calmodulin kinase and AKT, two oncogenic signaling pathways are activated by NPTX2 via calcium influx.

MedicalResearch: Were any of the findings unexpected?

Dr. Copland: When we started this project, we weren’t expecting to find a gene that is normally studied in the context of neuronal cell function to be playing a tumorigenic role in kidney cancer. It reiterated how complex of a disease this cancer really is. We also were surprised to find that NPTX2 is expressed in all tumor tissues regardless of stage and it is not expressed in normal kidney tissue. Thus, we discovered a new cancer gene with tumor specific expression in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC).

One of the most striking findings was that after looking at our own data as well as genomic profiling of kidney cancers published by other research groups, we found that NPTX2 was not only the most consistently overexpressed gene in this cancer, but it demonstrated the highest level of gene expression: 50-100+ times higher than normal kidney tissue. It is the most associated gene with clear cell renal cell carcinoma. What is also really unique is that NPTX2 expression appears to be specific for the clear cell subtype of kidney cancer and not other kidney cancer subtypes. NPTX2 could be potentially used as a blood biomarker to diagnose and confirm ccRCC since it is a secreted protein. The clinical potential of a targeted therapy against NPTX2 may benefit a large proportion of kidney cancer patients.

MedicalResearch: What should clinicians and patients take away from your report?

Dr. Copland: Kidney cancer, especially the clear cell subtype, is renowned for not only being highly metastatic, but also for being resistant to chemotherapy, radiation, and current targeted therapies available. What is worse is that disease recurrence occurs in 20 to 30% or more patients, even those who are originally diagnosed with early stage disease. There is no curative treatment for metastatic kidney cancer save for a very small percentage (~5%) of patients who respond to interleukin 2 immunotherapy.

We believe that targeted therapy against NPTX2 may provide a new avenue to treat this disease. The NPTX2 protein is a tumor-specific secreted protein, which opens the possibility for designing antibodies, small molecule inhibitors, or even inhibiting peptides against it. This will allow us to specifically block NPTX2, resulting in a lower risk of off-target effects.

Additionally, because each subtype of kidney cancer is independently unique, specific treatment strategies are required. Accurately diagnosing a patient with a specific subtype of kidney cancer is the first step in providing appropriate care. Given its unique expression pattern, NPTX2 could potentially serve as a biomarker to support accurate diagnoses or possibly even predict disease aggressiveness. Taken together, this will allow clinicians to facilitate individualized therapy, leading to better patient outcomes.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Dr. Copland: The next steps may involve developmental effort to create specific inhibitors against NPTX2, as well as test their efficacy and safety. Further characterization of its molecular mechanism of action is of interest. Development of NPTX2 as a diagnostic blood biomarker as well as a biomarker for response to therapy for ccRCC is also a new direction. Future research may also investigate the potential role of NPTX2 in other cancers. Interestingly, publications indicate that NPTX2 plays a tumor suppressor role in pancreatic cancer.

As cancer researchers, our bottom line is to identify ways to improve patient care by refining current therapies, developing new treatments, and facilitating accurate patient diagnoses in an effort to not only increase overall survival, but more importantly to find effective therapies that do not impair the quality of life of patients. Our hope is that NPTX2 inhibitors find their way into the clinic, and become part of the arsenal of therapies physicians can use to treat patients with not only kidney cancer, but potentially other cancers as well. We suspect neutralizing antibody therapy targeting NPTX2 will lead to relatively safe and efficacious therapy used in combination with other targeted therapies to enhance the lives of those diagnosed with metastatic ccRCC.

Citation:

Christina a Von Roemeling, Derek C. Radisky, Laura a Marlow, Simon J Cooper, Stefan Kg Grebe, Panagiotis Z Anastasiadis, Han W Tun, and John A. Copland. Neuronal Pentraxin 2 is a regulator of clear cell renal cell carcinoma malignancy through activation of the AMPA-selective glutamate receptor 4. Cancer Research, June 2014 DOI: 10.1158/0008-5472.CAN-14-0210