b'Redefining Research & Careengineered and is characterizing micePET (positron emission tomography) scan from LOOKING FOR NEW TARGETS YM. The scan, which uses labeled glucose, shows with mutations in the LATS1 and themassive uptake in the patients tumor throughout LATS2 genes in their kidneys. TheExploiting a mutant metabolic pathway the abdomen (yellow signal). The patients cancer cells had lost FH, interrupting the TCA cycle Carroll team has found that inactivationin tumor cells, causing a reliance on a second of the LATS genes causes renal cancersenergy generation pathwayglycolysiswhich could be blocked with an experimental drug, that metastasize. In July 2009, a 24-year-old mothermutated gene. This gene, called FH2DG. (Yamasaki et al., Nat Rev Urol, 2011)The team also discovered that the(called YM here) was referred to(fumarate hydratase), is one of 22,000 or genes YAP and TAZ are required forUT Southwestern with a 17-inch tumorso genes that constitute the human the development of these tumors.in her left kidney that occupied most ofgenome. When it is mutated, it predis- that block glycolysis, Dr. Brugarolas found Accordingly, YAP and TAZ may repre- her abdomen. The tumor was bleedingposes to pRCC-2. In familial cases, aa company, Threshold Pharmaceuticals, sent cancer vulnerabilities that treatmentand the patient was quite anemic withdefective copy of the gene is passed onthat had developed such a drug. could exploit.red blood cell counts down to 20 per- from parent to offspring. This conditionGlycolysis breaks down glucose, and the cent of normal. is called HLRCC (hereditary leiomyoma- drug was a modified version of glucose At UT Southwestern, interventionaltosis and renal cell cancer). Thethat would clog the process. The drug, radiologists threaded a catheter insertedcondition is quite rare, with only 300 orwhich is called 2DG (2-deoxy-glucose), REACHING BEYONDthrough the groin to the bleeding artery,so families described worldwide. enters cells but cannot be broken down, CONVENTION where they deployed clogging materialHowever, the patient was the onlythus blocking the chemical machinery to stop the bleeding.one in her family to get cancer, and bothresponsible for energy generation.Most of the research around RCCThe procedure was successful. Fourher parents were alive and well. To determine whether the approach has focused on genes (e.g., pro- weeks later, after blood counts hadNevertheless, Dr. Brugarolas decidedthe mother in the egg), and one of the twotemsirolimus, was quite familiar tocould work, Dr. Yamasaki, a urologist in tein coding genes). However, theseincreased, the patient underwentto probe further. He reasoned thatcopies was faulty. Further, as typicallyDr. Brugarolas. The drug worked, butthe Brugarolas lab, obtained FH-deficient genes make up only 1 percentsurgery to remove the tumor. It was aperhaps YM was the first one in heroccurs with cancer genes like FH, theunfortunately after only a few months thekidney cancer cells from Dr. W. Marston of the genome and other geneticmassive effort by Dr. Ganesh Raj and hisfamily to have developed the condition.remaining normal copy was lost in thecancer started to grow again.Linehan at the National Cancer Institute elements are likely to also play ateam. The kidney with the tumor wasThis would be the case if the mutationcancer cells. Only the faulty gene wasDr. Brugarolas then turned to theand tested the effects of 2DG. role. Dr. Josh Mendell, togetherremoved, along with some of thehad occurred in the sperm or the eggpresent.biology. FH normally functions in anReassuringly, 2DG stopped their growth. with Dr. Tu Dan in Dr. Mendellspancreas, the spleen, and part of thethat gave rise to her. Such a mutationThus, the patient was diagnosed withenergy production line that breaks downThe investigators wrote a report laboratory, is investigating thecolon. She recovered, but post-opwould be found only in her, but it wouldHLRCC, the first member of her family tonutrients to extract energy. Because onlypetitioning the FDA to authorize 2DG role of long noncoding RNAsscans showed that the cancer hadbe in all of her cells, which descendget the disease. Her daughter, a toddler,the faulty copy remained in the tumor, thetreatment for the patient. The FDA (lncRNAs). Unlike conventionalspread. She had stage 4 metastaticfrom the fertilized egg. The fertilized egghas a 50 percent chance of havingassembly line would stall. As a result,approved the request, and Threshold genes, lncRNAs are not translatedkidney cancer. copies its genetic information and theninherited it.cancer cells had to rely on another energyPharmaceuticals made 2DG available to into proteins. To understand theSurprised that a 24-year-old wouldsplits into two. The two cells do the sameUnfortunately, the condition is so raremanufacturing processglycolysis. TheYM. Given that one copy of FH was contribution of lncRNAs to kidneydevelop such an advanced cancer, herin turn, and split into four. This process isthat there are no treatments. However, aincreased reliance on glycolysis was seendefective in all her cells, 2DG was started cancer, Drs. Dan and Mendell firstdoctor, Dr. Brugarolas, set out tocarried out throughout gestation, infancy,drug had been approved by the Food andby Dr. Brugarolas and his team asat low doses and progressively increased compared the levels of lncRNAsinvestigate. The tumor was a relativelyand adulthood.Drug Administration that had shownpresenting an opportunity to attack theunder direct medical supervision. in tumors and normal kidney sam- infrequent tumor, a pRCC (papillaryTo test whether this might be theactivity against kidney cancers regardlesscancer. Dr. Brugarolas partnered with ples using UTSW Kidney Cancerrenal cell carcinoma) of high grade (seecase, a blood test was performed. Hisof type (see page 35). The drug,While there are no drugs in the clinicDr. DeBerardinis to monitor the effects of Explorer (see page 69) and Thepage 67). These tumors, referred to asconcerns proved correct: the FH gene2DG. At higher doses, YM started Cancer Genome Atlas. Next, theypRCC-2 tumors can run in families andwas defective. Normal cells have twodeveloping symptoms such as sweating assessed the role of deregulateddevelop at a young age. They arise as acopies of each gene (one from the fatherand blurred vision, indicating that energy lncRNAs using the CRISPR/Cas9result of a deficient instruction, acarried in the sperm and another fromgeneration was being blocked. However, genome-editing system. Theyeven at high levels, her tumor did designed a customized library ofnot respond. guide RNAs to target each lncRNADespite 2DGs efficacy against tumor that was overexpressed in tumors2 cells in the lab, it was not effective enough and conducted a pooled screen.B in the patient. (Yamasaki et al., Nat Rev Using massively parallel sequenc- Urol, 2011)ing approaches, they identifiedT CT scan from B 24-year-old The effort to save this patient was lncRNAs that were implicated inmother with cancer cell growth. If success- L massive fluid- monumental. It illustrates the commit-TL K filled tumor.ment of the members of the Kidney ful, their research may not onlyK Legend: provide novel insights into ccRCC(T) tumor,Following a fellowship in urologic oncology at Memorial SloanCancer Program to find a cure, even (B) bowel,Kettering, Dr. Aditya Bagrodia returns to UT Southwestern.when that means thinking outside the development and progression, but(K) kidney, Original Size er. box.Dr. Ralph DeBerardinispotentially also novel drug targets. (L) liv44 45'