"A new class of drugs called HIF inhibitors is more effective and better tolerated than the standard of care drug sunitinib in treating kidney cancer researchers with the Kidney Cancer Program at Harold C. Simmons Comprehensive Cancer Center have found.  HIF inhibitors which grew out of research begun more than  years ago at UT Southwestern Medical Center work by interfering with processes that fuel the growth of cells.  Investigators conducted a preclinical trial in mice transplanted with kidney cancer from over  patients and showed that the HIF inhibitor PT controlled cancer in half of the tumors according to a study published in the journal Nature.  This is a completely new treatment for kidney cancer. We want to make HIF inhibitors available to patients and are currently carrying out clinical trials said Dr. James Brugarolas Director of the Kidney Cancer Program who is leading an  million SPORE grant from the National Cancer Institute seeking to translate new discoveries into novel therapies for kidney cancer patients. Part of the SPORE grant one of just two directly related to kidney cancer in the nation is focused on further researching HIF inhibitors. In a previous report Dr. Kevin Courtney Assistant Professor of Internal Medicine and a coauthor of the current study reported at the American Association of Clinical Oncology annual meeting that HIF inhibitors were safe in patients and had activity even in heavily pretreated patients. In the study in Nature investigators show that HIF inhibition was able to control metastatic kidney cancer even after  lines of prior therapy. See video.  The findings show that HIF is a promising target to combat kidney cancer said Dr. Brugarolas senior author and a Virginia Murchison Linthicum Scholar in Medical Research at UT Southwestern. Nearly  Americans are now living with a diagnosis of kidney cancer and more than  people are expected to be diagnosed with kidney cancer this year according to the National Cancer Institute. Texas has the fifth highest rate of this cancer in the U.S.  What is HIF  HIFs or hypoxiainducible factors like HIF allow the bodys cells to adjust to lowoxygen environments. HIFs activate programs that promote the development of blood vessels facilitate oxygen delivery and promote efficient nutrient utilization. Kidney cancer cells hijack the same system to fuel their growth.  HIF inhibitors work by suppressing the effects of HIF which include downregulating an important protein called VEGF that promotes the formation of blood vessels needed for tumors to grow. Unlike existing VEGF inhibitors the HIF inhibitor blocks VEGF only in the cancer and therefore does not cause cardiac toxicity or hypertension Dr. Brugarolas explained. New HIF findings  In the Nature study researchers compared the two drugs head to head and found that the HIF inhibitor was more active than sunitinib and that it was active against tumors progressing on sunitinib. Furthermore it was also better tolerated. As sometimes happens in patients mice on sunitinib were sickly and lost weight whereas mice on the HIF inhibitor gained weight while on the study he said. Researchers surprisingly found a subset of tumors that do not respond to the drug but were able to identify biomarkers that once verified would help determine which patients are more likely to benefit from HIF therapies. HIF is believed to be the most important driver of kidney cancer. Traditionally proteins like HIF were disregarded as drug targets because their shape made it nearly impossible to design drugs against them Dr. Brugarolas said. The approaches we have taken pave the way for identifying drug candidates for other proteins that have traditionally been considered undruggable. HIF also appears significant in other types of cancer including deadly brain cancers called glioblastomas and nonsmall cell lung cancer the most common type of lung malignancy. How HIF came to be  In  UT Southwestern researchers Dr. Steven McKnight Chairman of Biochemistry and molecular geneticist Dr. David Russell Vice Provost and Dean of Basic Research led research discovering and describing the protein encoded by the EPAS gene also known as HIFa the main HIF component. Over the course of a decade the laboratories of Dr. Richard Bruick Professor of Biochemistry holder of the Michael L. Rosenberg Scholar in Biomedical Research and a coauthor of the current study and Dr. Kevin Gardner Adjunct Professor of Biochemistry solved the structure of HIFa.  By  researchers had identified a sweet spot where drugs could bind and shut down HIF activity. Using the Simmons Cancer Centers HighThroughput Screening scientists tested more than  chemicals to see which ones could interfere with HIF identifying several potential druglike compounds. The most promising compounds were licensed to Peloton Therapeutics Inc. a biotech firm cofounded by Dr. McKnight and based at UT Southwesterns BioCenter campus. In  the first HIF inhibitor an oral drug known as PT entered clinical trials in patients with advanced or metastatic renal clear cell carcinoma.  HIF inhibitors also are the target of UTSWs recent  million SPORE Specialized Program of Research Excellence award. Investigators will further biomarkers to identify patients most likely to respond to the HIF inhibitor as well as to anticipate ways in which the tumor may evade the drugs impact. UT Southwesterns SPORE program involves four innovative disease and clinical research teams targeting adult and pediatric kidney cancer. Other UTSW SPORE investigators are looking at the function of a gene that identifies a cluster of particularly aggressive tumors in hopes of identifying vulnerabilities that can be targeted with drugs examining kidney cancer metabolism to distinguish aggressive from less active tumors potentially yielding a tailored treatment approach and evaluating novel subtypes of childhood kidney cancer. The HIF research team  The Nature research was supported by grants from the National Institutes of Health including the SPORE Peloton Therapeutics Inc. and the Cancer Prevention and Research Institute of Texas the National Center for Advancing Translational Sciences Center for Translational Medicine National Natural Science Foundation of China and philanthropy including the Tom Green Memorial fund.  More than  researchers contributed to the study including Dr. Payal Kapur Associate Professor of Pathology Dr. Ivan Pedrosa Associate Professor of Radiology in the Advanced Imaging Research Center who holds the Jack Reynolds M.D. Chair in Radiology Dr. Xiankai Sun Associate Professor of Radiology in the Advanced Imaging Research Center who holds the Dr. Jack Krohmer Professorship in Radiation Physics Dr. XianJin Xie Professor of Clinical Sciences Dr. Yang Xie Associate Professor of Clinical Sciences Dr. Tae Hyun Hwang Assistant Professor of Clinical Sciences Dr. Guiyang Hao Assistant Professor of Radiology Dr. Eugene Frenkel Professor of Internal Medicine and Radiology who holds the Raymond D. and Patsy R. Nasher Distinguished Chair in Cancer Research in Honor of Eugene P. Frenkel M.D. the Elaine Dewey Sammons Distinguished Chair in Cancer Research in Honor of Eugene P. Frenkel M.D. and the A. Kenneth Pye Professorship in Cancer Research and Dr. Rene M. McKay Director of Research Administration for the Kidney Cancer Program. Additional UT Southwestern researchers include lead authors Dr. Wenfang Chen Haley Hill Alana Christie and Min Soo Kim as well as Eboni Holloman Andrea PaviaJimenez Farrah Homayoun Dr. Yuanqing Ma Dr. Nirav Patel Dr. Guiyang Hao Qurratulain Yousuf Allison Joyce Dr. He Zhang and Jenny Chang.  Disclosures coauthors Tai Wong James P. Rizzi Eli M. Wallace Naseem Zojwalla and John A. Josey are employees and own equity in Peloton Therapeutics Inc. Kevin Gardner and Richard Bruick have licensed IP consult for and own equity Min Soo Kim Tae Hyun Hwang Yang Xie and James Brugarolas are authors on a filed patent pertaining biomarkers of the HIF inhibitor. UT Southwestern Medical Center owns stock in Peloton Therapeutics and has a financial interest in the intellectual property used within the research.  The Harold C. Simmons Comprehensive Cancer Center is the only NCIdesignated comprehensive cancer center in North Texas and one of just  NCIdesignated comprehensive cancer centers in the nation. Simmons Cancer Center includes  major cancer care programs. In addition the Centers education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only  U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site. About UT Southwestern Medical Center  UT Southwestern one of the premier academic medical centers in the nation integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty includes many distinguished members including six who have been awarded Nobel Prizes since . The faculty of almost  is responsible for groundbreaking medical advances and is committed to translating sciencedriven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about  specialties to more than  hospitalized patients and oversee approximately . million outpatient visits a year."