b'Redefining Research & CareMolecularly Targeted DrugsProbing kidney cancers biological underpinnings has driven arevolution in treatment.Program Director Dr. Brugarolas was initially drawn to kidney cancer research because of the dearth of treatment options. In 2003, when he finished his oncology training at the Dana-Farber Cancer Institute/Harvard Cancer Center, there was just one treatment for kidney cancer patients: IL-2 (interleu-kin-2). However, IL-2 is quite toxic and typically administered in an intensive care unit. Few patients could tolerate it. Equipped with a Ph.D. in cancer biology from MIT, he set out to study the biology of the disease, convinced it was the key to new therapies.While at Dana-Farber, he joined the laboratory of Dr. William Kaelin, a pioneer in kidney cancer research and recipient of the The latest CyberKnife2019 Nobel Prize in Physiology or Medicine. technology to deliver focusedSchematic of a kidney tumor (renal Dr. Kaelin had discovered that the gene VHLcell carcinoma) of clear cell type with and ablative radiation for kidney cancer metastasis.(von Hippel-Lindau), inactivated in most adultderegulated pathways and targeting drugs. Inactivation of VHL leads to activation kidney cancers, regulates HIF (hypoxia-development and eventual FDA approvalof HIF. This drives the production of inducible factor) (see page 36). HIF activationof drugs that neutralize VEGF (bevaci- VEGF, which activates the VEGF receptor (VEGFR2) on the surface of blood vessel in cancer cells promotes the development ofzumab [Avastin]), or block its effects oncells, instructing them to proliferate and blood vessels, which carry oxygen and nutri- the blood vessel cells by inactivating itsmake more blood vessels. Drugs that interfere with these processes appear here ents to the cancer and support its expansion.receptor (sorafenib [Nexavar], sunitinibin red, with blunted ends showing where In response to HIF, cancer cells make VEGF[Sutent], pazopanib [Votrient], axitinibthey block. (Adapted from Brugarolas, When Kidney Cancer Spreads (vascular endothelial growth factor). VEGF is[Inlyta], cabozantinib [Cabometyx], andJ. Renal Cell CarcinomaMolecular Pathways and Therapies, The New released from the cancer cells and binds to alenvatinib [Lenvima]). These drugsEngland Journal of Medicine, 2007)protein on the surface of blood vessel cells,interfere with the formation of new blood Surveillance for colleagues are performing genomic analysesled by Dr. Rini and analyses of their tumorssending a signal for them to grow. vessels. They are broadly referred to as Slow-growing Kidney Cancers on tumors from patients with slowly growingmay help identify similar patients who mayThese discoveries enabled theblockers of angiogenesis, coming from Some kidney cancers grow slowly eventumors. These patients participated in a pro- be good candidates for active surveillance. after they have spread. Physicians familiarspective clinical trial of active surveillance(Rini et al., Lancet Oncol, 2016) 2007with the disease learn to recognize themTemsirolimusand may recommend active surveillancea2005 2012careful monitoring program. In appropriateSorafenib Axitinib 2016instances, delaying treatment can spareAIMING STEREOTACTIC RADIATION CabozantinibDrug approvals by the Food patients debilitating side effects and theTO TARGET LIMITED SPREAD and Drug Administration forLenvatinibexpense of cancer drugs.advanced kidney cancer.1992 2019UT Southwestern investigators havewhich comes from the Greek oligos,IL-2 AvelumabChallenge: Pinpointing developed a program to treat kidneymeaning few.PembrolizumabIndolent Tumorscancer with limited spread using SBRT.A clinical trial ongoing at UTSW1970 1980 1990 2000 2010 2020Researchers are investigating why someThis approach lets physicians targetseeks to better understand how2018kidney cancers grow slowly after spreading.individual metastases with highlypatients benefit from this approach.2006 IpilimumabIn a partnership with Dr. Brian Rini, for- focused radiation, sparing patients(Wang et al., Int J Radiat Oncol BiolSunitinib 2015mer Director of the Genitourinary Programdrug therapy and its side effects. ThesePhys, 2017; Zhang et al., Int J RadiatNivolumabat Cleveland Clinic Cancer Center andtumors are known as oligometastatic,Oncol Biol Phys, 2019)2009Bevacizumabnow Clinical Trials Chief at Vanderbilt- EverolimusIngram Cancer Center, Dr. Brugarolas andPazopanib34 35'