Branimir Ivan "Brandy" Sikic (born October 18, 1947 [1] ) is an American medical doctor and scientist at Stanford University School of Medicine. He is an oncologist and cancer pharmacologist, and has served as a faculty member at Stanford University since 1979. His research spans basic, translational, and clinical research and investigates the mechanisms of drug resistance and the development of new anticancer therapies.
Sikic was born in Graz, Austria, on October 18, 1947. His parents were refugees from Croatia, his father a mathematician and his mother a linguist. The family emigrated to Adelaide, Australia in 1949, and to Cincinnati, Ohio in 1956. [2] Sikic graduated from St. Xavier High School as president of his class in 1964 at age 16, [3] and attended Georgetown University in Washington, D.C., where he obtained a B.S. degree in biology in 1968. [4]
Sikic attended the University of Chicago Pritzker School of Medicine, graduating with an M.D. in 1972. He returned to Georgetown University Hospital in Washington, D.C. for an internship and residency in internal medicine (1972-5). From 1975 to 1978 he was a postdoctoral laboratory research fellow at the National Institutes of Health (NIH), working on the regulation of drug metabolism and the pharmacology and pulmonary toxicology of the anticancer drug bleomycin. He returned to Georgetown in 1978–9 to complete a clinical fellowship in medical oncology, prior to joining the faculty at Stanford University. [4]
In 1992 Sikic began directing the General Clinical Research Center and then the Center for Clinical and Translational Research [5] in 2008. He is the founder and director of the Central European Oncology Congress held in Opatija, Croatia since 1998. On January 9, 2010, he was awarded the Katarina Zrinska Medal for Science and Medicine by the President of Croatia. [6]
Sikic has made significant contributions to understanding the biology and clinical significance of multidrug resistance (MDR), particularly the P-glycoprotein (P-gp) multidrug transporter and regulation of the ABCB1 gene. [7] He discovered that deletion of aa335 changes the drug-binding spectrum and is integral to the pharmacophore of P-gp. [8] He also defined specific sites of transactivation of ABCB1, and mechanisms of amplification of the gene. [9] [10]
The laboratory work on drug resistance mechanisms led to a series of clinical Phase I-III trials that defined this field. [11] Early on, Sikic's group found that P-gp inhibition resulted in significant pharmacokinetic alterations of several anticancer drugs, with the potential for markedly increased toxicities unless doses were adjusted. [12] These findings, and the co-existence of other resistance mechanisms in human cancers, redefined the field and demonstrated the limited clinical utility of MDR modulation. [13] [14]
The Sikic group utilized gene expression profiling and systems biology to yield insight into cancer taxonomy and prognostic and predictive signatures for cancer therapies. [15] [16] [17] With their colleagues Olivier Gevaert and Sylvia Plevritis, they have identified driver genes for ovarian cancers. [18] [19]
P-glycoprotein 1 also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein of the cell membrane that pumps many foreign substances out of cells. More formally, it is an ATP-dependent efflux pump with broad substrate specificity. It exists in animals, fungi, and bacteria, and it likely evolved as a defense mechanism against harmful substances.
Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from Streptomyces bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder cancer, and lung cancers. The first anthracycline discovered was daunorubicin, which is produced naturally by Streptomyces peucetius, a species of Actinomycetota. Clinically the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin.
Topotecan, sold under the brand name Hycamtin among others, is a chemotherapeutic agent medication that is a topoisomerase inhibitor. It is a synthetic, water-soluble analog of the natural chemical compound camptothecin. It is used in the form of its hydrochloride salt to treat ovarian cancer, lung cancer and other cancer types.
Cediranib is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases.
Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB).
Satraplatin is a platinum-based antineoplastic agent that was under investigation as a treatment of patients with advanced prostate cancer who have failed previous chemotherapy. It has not yet received approval from the U.S. Food and Drug Administration. First mentioned in the medical literature in 1993, satraplatin is the first orally active platinum-based chemotherapeutic drug; other available platinum analogues—cisplatin, carboplatin, and oxaliplatin—must be given intravenously.
ATP-binding cassette super-family G member 2 is a protein that in humans is encoded by the ABCG2 gene. ABCG2 has also been designated as CDw338. ABCG2 is a translocation protein used to actively pump drugs and other compounds against their concentration gradient using the bonding and hydrolysis of ATP as the energy source.
Major vault protein is a protein that in humans is encoded by the MVP gene. 78 copies of the protein assemble into the large compartments called vaults.
Semaphorin-3C is a protein that in humans is encoded by the SEMA3C gene.
Genta Incorporated was a biopharmaceutical company started in La Jolla, California, which discovered and developed innovative drugs for the treatment of patients with cancer. Founded in 1989 by a highly skilled entrepreneur, the company focused on a novel technology known as antisense, which targets gene products that are associated with the onset and progression of serious diseases. At that time, only Ionis Pharmaceuticals, Inc. was conducting significant research with this technology. Antisense is a short span of oligonucleotides – modified DNA structures ranging from about 12-24 bases that selectively bind to specific RNA. The intent is to block expression of an aberrant protein that contributes to the disease of interest. Genta in-licensed three different antisense molecules that blocked Bcl-2, a fibroblast growth factor (FGF), and the gene c-myb, respectively.
Hani Gabra PhD FRCPE FRCP is a British oncologist and Professor Emeritus in Medical Oncology at Imperial College London.
Temozolomide (TMZ), sold under the brand name Temodar among others, is a medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. It is taken by mouth or via intravenous infusion.
Motesanib is an experimental drug candidate originally developed by Amgen but later investigated by the Takeda Pharmaceutical Company. It is an orally administered small molecule belonging to angiokinase inhibitor class which acts as an antagonist of VEGF receptors, platelet-derived growth factor receptors, and stem cell factor receptors. It is used as the phosphate salt motesanib diphosphate. After clinical trials in thyroid cancer, non-small cell lung cancer, gastrointestinal stromal cancer, colorectal cancer, and breast cancer, the drug was not found to show sufficient efficacy for further development, and development was abandoned by Takeda.
Tubulin inhibitors are chemotherapy drugs that interfere directly with the tubulin system, which is in contrast to those chemotherapy drugs acting on DNA. Microtubules play an important role in eukaryotic cells. Alpha- and beta-tubulin, the main components of microtubules, have gained considerable interest because of their function and biophysical properties and has become the subject of intense study. The addition of tubulin ligands can affect microtubule stability and function, including mitosis, cell motion and intracellular organelle transport. Tubulin binding molecules have generated significant interest after the introduction of the taxanes into clinical oncology and the general use of the vinca alkaloids. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization or depolymerization into the microtubules. This mode of action is also shared with another natural agent called colchicine.
Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.
Michelle Haber is an Australian cancer researcher.
Cancer treatments may vary depending on what type of cancer is being targeted, but one challenge remains in all of them: it is incredibly difficult to target without killing good cells. Cancer drugs and therapies all have very low selective toxicity. However, with the help of nanotechnology and RNA silencing, new and better treatments may be on the horizon for certain forms of cancer.
Luis Alberto Diaz, Jr. is the Head of the Division of Solid Tumor Oncology in Memorial Sloan Kettering’s Department of Medicine.
Jung-Min Lee is a South Korean-American medical oncologist and physician-scientist focused on the early clinical drug development and translational studies of targeted agents in BRCA mutation-associated breast or ovarian cancer, high-grade epithelial ovarian cancer, and triple-negative breast cancer. She is a NIH Lasker Clinical Research Scholar and principal investigator in the Women's Malignancies Branch at the National Cancer Institute.
Roy S. Herbst is an American oncologist who is the Ensign Professor of Medicine, Professor of Pharmacology, Chief of Medical Oncology, and Associate Director for Translational Research at Yale Cancer Center and Yale School of Medicine in New Haven, Connecticut.
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