Two young teen-agers recovering from kidney cancer serendipitously helped discover the oncogene responsible for the brand of renal cell carcinoma from which surgery had rescued them.
"The index case I saw was an 18-year-old female with a history of obesity, hirsutism and polycystic ovary syndrome," recalled pediatric oncologist David Fisher at Harvard-affiliated Dana-Farber Cancer Institute in Boston. "A right renal mass was detected, and partial nephrectomy performed. The patient was well without evidence of recurrent neoplastic disease at 18 months follow-up.
"The second case was a young man, also 18, with a 7-centimeter left renal mass, also removed by surgery. The similarity there," Fisher continued, "was also a papillary renal cell carcinoma with the same abnormal chromosomal translocation. Papillary renal cell carcinoma," he noted, "is the most common kidney carcinoma in children.
"The good news, "Fisher continued, "is that all cancer in children is rare. The common types of malignancy are mostly adult cancers - lung, breast, colon, prostate, things of that nature. Onset of papillary renal cell carcinoma [PRCC] usually occurs in teen-age years or young adults - on the borderline between pediatric and adult. And there's a reasonable chance, if caught early enough, that this tumor can be cut out surgically, in which case the problem with this particular type of tumor is that failure to successfully excise it surgically means it's not a chemotherapy-responsive tumor.
"Many pediatric cancers nowadays," Fisher went on, "are actually very responsive to chemotherapy, and even curable - unfortunately, unlike many adult cancers. PRCC is not one of the tumors whose chemotherapy sensitivity is good; it's actually very poor - like many adult cancers. That's the reason we wanted to know the oncogene that's responsible, because we'd love to be able to target that molecule with drugs, and specifically disrupt its activity."
From Minuscule To Grapefruit-Size Tumors
"The tumor will occur in one of the kidneys," Fisher explained. "It can be anywhere from a very small lesion to a massive grapefruit-size tumor. So unfortunately there might be some propensity for the tumor to grow to significant size before it would be detected. It could cause blockage of the urinary tract or intestinal strangulation. A common complaint is bleeding into the urine stream, but that can be hard to notice. So it can be one of these relatively silent tumors, unfortunately."
Fisher, an associate professor of pediatric oncology at Harvard Medical School, is senior author of a seminal report in the Proceedings of the National Academy of Sciences (PNAS), released online April 29, 2003. Its title: "Cloning of a novel Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation."
"Our paper's overall finding," Fisher told BioWorld Today, "was the discovery of a new oncogene, which happened to be found in that index patient's papillary renal cell carcinoma. Basically, it's a brand new oncogene. We identified a recurrent chromosome translocation, which has been identified in multiple patients with this disease. The culprit was not previously known, and due to some fortuitous observation that we happened to make from some other experiments going on in our lab, we thought, Aha! It must be this oncogene,' and we tested it until we knew what it was. TFEB is a most likely major culprit. Our presumption is that this oncogene is causative for the malignancy of the tumor," Fisher observed.
"Discovery of that TFEB oncogene actually came from that female patient, who I saw at the hospital here, in the clinic, sometime last summer. It was one of these epiphanies," Fisher remembered, "that literally reading through her chart, a feature of the pathology report, there was only one explanation that could put all this together. So the idea came from examining the patient and the pathologic features of her tumor. It was over the following four or five months or so that the actual cloning and identification of the oncogene was made, first in her tumor, then in others as well. The hope here is that we're really getting to the core of what's driving the tumor cells, and thereby can identify targets that could be therapeutic.
"The oncogene TFEB was found to be translocated in a subset of the papillary group," Fisher recounted. "Nowadays, every tumor under the sun is being subclassified. It used to be that everything was just classified by what the cells looked like under the microscope. Now in the molecular era, in the biotech era, everything is analyzed more and more by gene expression data, by what chromosomal abnormalities, what oncogenes there are. In renal carcinomas, some fraction will turn out to have this TFEB translocation. We don't formally know yet what fraction it is. We know that it's recurring in a number of patients worldwide. It's been described in multiple papers, and we know that TFEB is involved at that translocation."
Ongoing Watchword: Therapeutic Druggability
Fisher summed up the ongoing projects that he and his lab team are now undertaking: "There are two major directions," he noted. "One is to understand how TFEB and this specific chromosomal translocation can be used to improve diagnostic accuracy and classification of renal tumors. When you identify a molecular event that refines your way of looking at a specific disease, it can allow you to examine patients, who examine treatment options, who examine the natural history. One thing is to use this information to better understand the presentation and diagnosis of this renal tumor.
"The second area we're focusing in," he said, "is equally important. It's to use the TFEB information, which is probably the endpoint driving the cancerous behavior of the cells. We will try to identify druggable therapeutic targets. Our presumption is that if we were to disrupt TFEB within these tumors, that is a very reasonable chance that the tumor couldn't survive. That would have therapeutic benefit."
Fisher is "definitely planning to test such drugs in preclinical animals. We have mice in which we can inject human tumor cells and they are able to form the tumors, so we can actually study the human tumor in an in vivo mouse setting. That's a good part of the analysis we're involved in at this moment."