b'Redefining Research & CareOH OHCH 3 CH 3CH 3 CH 3 O OOH OH H 3 C H 3 C O OO O O O O CH 3 CH 3N ON H H O O 3 N H N H H H O H OROBOTS SUPPORTING DRUG DISCOVERY H 3 C O H 3 C OO O OO OCH 3 CH H 3 C O H 3 C O OO H OO O and the patient was profoundly anemic O OO HOC H 3 C O HOC H 3 COH OH 3 OH OH HO HO 3 OH OH (blood counts below 25 percent of normal). Building on the vision of Steventreatments. The facility contains moreThe HTS laboratory is also able toH 3 C H 3 C H 3 C H 3 CH H 3 CH 3 O O O H H O CH 3 O O O Left alone, death was likely within days.McKnight, Ph.D., and with supportthan 330,000 compounds, including pro- leverage its infrastructure to performO CH O O CH 3O OCH 3 CH 3 H 3 C H 3 C 3 CH 3 H 3 C H 3 C H 3 C H 3 C CH 3 Patients with familial tuberous sclerosis from Dr. James Willson, the Directorprietary compounds, and has completedgene inactivation analyses. Using bits ofCH The kidney cancerCH 3 complex have a mutation in either TSC1 of Simmons Comprehensive Cancermore than 100 screens, filed 18 patents,genetic material, the lab can disable eachCH 3 CH 3 approved drugCH 3 CH 3 or TSC2 in all of the cells in their body (see temsirolimus is converted Center at the time, UT Southwesternand has licensed several compounds toof the approximately 22,000 genes inTemsirolimus to sirolimus in the body.SirolimusSirolimuscreated a facility able to test hundreds ofthird parties.the human genome. These studies allowTemsirolimus page 60), which makes them more prone thousands of chemicals against cancer.Promising compounds are evaluatedinvestigators to identify cancer-promotingtargeting mTOR are used for the treatment75 percent of the temsirolimus was con- to develop cancer. This results in activa-Directed by Bruce Posner, Ph.D., theby medicinal chemists such as Josephand cancer-protective genes, as well asof kidney cancer (see page 35). Theseverted to sirolimus in the body. tion of mTOR in tumors, and, as such, facility is equipped with robots that sup- Ready, Ph.D. Once optimized, theypotential new targets for drug develop- drugs do not work for everyone, however.After a discussion with the patient,Dr. Brugarolas recommended trying an port high-throughput screening (HTS).are tested in animals in the Preclinicalment. (Whitehurst et al., Nature, 2007;An important question is, for whom do theyDr. Brugarolas offered sirolimus. SirolimusmTOR-blocking drug.Pharmaceutical companies often havePharmacology Core, led by NoellePhillips et al., J Med Chem, 2008; Wolff etwork best?dosing was adjusted so it matched the levelsWithin days, bleeding stopped. The such facilities, but they are uncommonWilliams, Ph.D. Subsequently, theseal., Oncotarget, 2015; Chen et al., Nature,In 2011, the Brugarolas team discoveredin the blood of cancer patients treated withresponse was remarkable. The patient went in academic centers. UT Southwestern,chemicals may be evaluated in mice2016; Eskiocak et al., Nat Commun,that the gene encoding TSC1 was mutatedtemsirolimus. It worked. The cancers growthhome, and his tumor continued shrinking. however, deploys its HTS laboratorytransplanted with human kidney tumors2016; Kim et al., Nature, 2016; Zhang et(inactivated) in some ccRCC. While thewas stopped. It was the first example of aThe tumor, which was initially the size of to help translate discoveries into new(see page 67).al., Sci Transl Med, 2016) frequency of TSC1 mutations in tumors waskidney cancer treated with sirolimus. a softball, diminished to the size of a golf low at only 5 percent, the investigators dis- Today, one month of sirolimus costsball, and the patient survived an additional covered that tumors with TSC1 mutations,10 percent of what temsirolimus costs.four years.which have particularly active mTOR, mayFurthermore, unlike temsirolimus, whichTogether with a combined study from the be most responsive to the mTOR-targetingis given intravenously, sirolimus is takenDana-Farber Cancer Institute and Memorial drugs. This research provides the first exam- orally. For parts of the world where financialSloan Kettering Cancer Center of three ple of how a mutated gene can be linked toresources are limited and modern medi- cases, this study from UT Southwestern, Bridging Key Pathways a particular treatment in kidney cancer. (Gaocations are not available, sirolimus couldwhich included a second case from in Renal Cancer and Pan, Genes Dev, 2001; Gao et al., Natprovide an alternative. Sirolimus could alsoDr. Thomas Bradley in New York, reported Pinpointing how pathways in cancer cellsCell Biol, 2002; Zhang et al., Nat Cell Biol,potentially be used in lieu of everolimus,for the first time the potential benefit of are coordinated could open new treat- 2003; Kucejova et al., Mol Cancer Res, 2011) a related drug also approved for kidneymTOR inhibitors for the treatment of EAML. Temsirolimus ment possibilities.cancer, which is quite expensive, says(Wolff et al., J Clin Oncol, 2010)Dr. Brugarolas and his team have foundAn Option for Kidney CancerDr. Mark Ratain, Director of the Center for that REDD1 (regulated by developmentTreatment Where Modern Personalized Therapeutics at the UniversityFEBRUARY 2009Sirolimus and DNA damage 1) links HIF and mTORDrugs Dont Reach? of Chicago, and member of the Scientific pathwaysthe most important pathways inIn 2006, a year after the removal of a ten- Advisory Board of the Kidney CancerLkidney cancer cells (see page 35).nis-ball-sized ccRCC tumor, a 66-year-oldProgram. (Brugarolas et al., J Clin Oncol,B 2Given the important role of REDD1,patient developed liver and lung metasta- 2008) Lbiophysicist Xuewu Zhang, Ph.D., wanted toses. Afflicted with various cardiovascularT S T B S1know what REDD1 looked like. He crystal- ailments and having a history of two priorHope Where There Was None K Kized REDD1, which unmasked its atomicstrokes, the man was a poor candidate forPhysicians at the Kidney Cancer Program blueprint. This showed that REDD1 is asunitinib, sorafenib, and IL-2, the three drugsare often confronted with difficult cases.Original Sizerather unique protein relative to all otherapproved by FDA at that time (see pageOften, they involve patients with kidney known proteins in the cell. (Brugarolas et al.,35). Temsirolimus, which wasnt approvedcancers for which no clear treatmentAPRIL 2013Genes Dev, 2004; Vega-Rubin-de-Celis etuntil 2007, had shown promise but was notoptions exist. al., Biochemistry, 2010; Kucejova et al., Molavailable at the time. The patients cancerFor instance, in 2009, a 24-year-old man2Cancer Res, 2011) was spreading fast, however, and he couldwith familial tuberous sclerosis complexTnot wait. came to UT Southwestern for evaluationL 1 2The Right Drug for the Right Patient In 1999, the FDA had approved anotherof an EAML (epithelioid angiomyolipoma).T K L T 1 T 2Schematic of REDD1 (and itsIn 2002, Duojia Pan, Ph.D., discovereddrug, sirolimus. Sirolimus was approved forEAMLs are rare tumors that arise fromKatomic blueprint) linking HIF and mTOR pathways in renal cancer.that mTOR is regulated by the TSC1 andan indication very different from cancer. Itsupport cells in the kidney. They have no HIF activates the production ofTSC2 proteins, which bind together. Whenwas approved as an immunosuppressant inknown treatment. REDD1, which, paradoxically, restrains mTOR. One way in whichTSC1/TSC2 is disrupted, mTOR becomespatients with kidney transplants, to preventThis was a recurrence. The originalCT scans from patient with an EAML tumor showingOriginal Sizetumor cells evade the effectsexcessively active, leading to the activationthe body from rejecting the new kidney. tumor had been removed just a few monthsan 80 percent tumor reduction after treatment with of REDD1 on mTOR is throughan mTOR inhibitor. After four years, a second tumor inactivation of TSC1/TSC2. (Vega-of HIF and increasing protein production byNevertheless, sirolimus was very similarearlier. In the span of five months, the tumoremerged that was resistant to the treatment and Rubin-de-Celis et al., Biochemistry,cells, including cancer cells. mTOR block- to temsirolimus, and both targeted mTOR.had grown to occupy half of the abdomen.eventually led to the demise of the patient. Legend: 2010; Brugarolas, N Engl J Med,(T1) EAML tumor, (T2) second tumor, (B) bowel, (K) 2007) ade stops cells from growing and two drugsFurthermore, a publication had shown thatBleeding was occurring inside the tumor,kidney, (L) liver, (S) spleen. (Wolff et al., J Clin Oncol, 2010)38 39'