WBR0374

Author	[[PageAuthor::Rim Halaby, M.D. [1] (Reviewed by Will Gibson) (Reviewed by Alison Leibowitz)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pharmacology
Sub Category	SubCategory::Renal
Prompt	[[Prompt::A 72-year-old Caucasian male presents to the ER with complaints of hematuria and back pain. The patient’s medical history is significant for hypertension, controlled with pirindopril, and diabetes mellitus type II, controlled with metformin. Upon physical examination you observe a palpable abdominal mass. After appropriate initial work-up, a renal biopsy is performed (the findings are displayed in the image below). If surgical intervention is not possible, which of the following pharmacological therapies is the best treatment for this patient’s condition? ]]
Answer A	AnswerA::Folic acid analog that inhibits dihydrofolate reductase
Answer A Explanation	[[AnswerAExp::The antimetabolite Methotrexate is not an effective treatment for renal clear cell carcinoma. Methotrexate is frequently used to treat hematologic malignancies.]]
Answer B	AnswerB::Pyrimidine analog that inhibits DNA polymerase
Answer B Explanation	[[AnswerBExp::The antimetabolit Cytarabine is not effective in the treatment of renal cell carcinoma.]]
Answer C	AnswerC::Alkaloid that blocks polymerization of microtubule in the M phase
Answer C Explanation	[[AnswerCExp::Microtubule inhibitors, such as vincristine and vinblastine, may be used to treat Wilms tumor and Hodgkins lymphoma.]]
Answer D	AnswerD::Calcineurin inhibitor that binds to FK-binding protein
Answer D Explanation	AnswerDExp::Tacrolimus, a calcineurin inhibitor that binds to FK-binding protein, is commonly used as an immunosuppressive agent for renal transplant recipients.
Answer E	AnswerE::Immune modulation by interleukin-2 recombinant therapy
Answer E Explanation	AnswerEExp::Aldesleukin (interleukin 2 recombinant cytokine) is an effective pharmacological therapy for patients with advanced renal cell carcinoma.
Right Answer	RightAnswer::E
Explanation	[[Explanation::Renal cell carcinoma, also termed clear cell carcinoma, is a malignant kidney cancer originating in the proximal convoluted tubule. In a localized tumor, partial or radical nephrectomy are first-line treatment options, depending on the size of the tumor. Approximately 30% of patients with renal cell carcinoma have metastatic disease on initial presentation. While conventional cancer therapy is typically ineffective, recombinant interleukin-2, (aldesleukin), has demonstrated clinical efficacy. IL-2 immunotherapy is approved for metastatic melanoma and renal cell carcinoma. Cancer cell genomes acquire obtain hundreds to thousands of mutations in the course of transformation from normal tissue to transformed cancer cell. Some of these mutations can cause changes to the structure of expressed proteins. When these proteins are degraded and presented on MHC class-II molecules, they form the antigenic basis for tumor-self distinction in cancer immunity. The mutations that compose this therapeutic window are referred to as neoantigens. IL-2 is thought to activate T-cells primed against tumor neoantigens and induce a powerful anti-tumor immune response in a subset of patients whose tumors contain immune-inducing mutations. Melanoma is particularly vulnerable to immunotherapy because while exposed to the sun, melanoma cells develop the highest median mutation rate of any known cancer. This abundance of mutations provides a fertile soil of neoantigens from which an immune response can grow. While IL-2 therapy provides a modest benefit to renal cell carcinoma patients analyzed as a whole, the individual responses to IL-2 therapy are often stunning. Only 5% of patients typically demonstrate tumor shrinkage, but those that do respond often see metastatic cancer regress entirely without remission. New therapeutic options, such as vascular endothelial growth factor (VEGF) inhibitors and mammalian target of rapamycin pathways, have also demonstrated clinical effectiveness in treating patients with metastatic renal carcinoma. A new generation of highly effective immunotherapeutic agents, PDL1 inhibitors are becoming increasingly widespread and may be tested on future releases of the USMLE. Genetically, renal cell carcinoma is characterized by nearly universal inactivation of the VHL tumor suppressor gene. VHL encodes a ubiquitin ligase that targets the HIF (hypoxia inducible factor) protein for degradation. In the absence of VHL protein, renal cell carcinoma cells turn on a transcriptional program mimicking that of an oxygen-deprived state. The cells begin to highly express genes such as VEGF (vascular endothelial growth factor) that induce tumorigenesis. Recall, that the kidneys are responsible for coordinating the erythropoetic response to low oxygen tension. Accordingly, renal cell carcinomas express high levels of erythropoietin and patients often develop high hematocrits. Educational Objective: Cytokine recombinant interleukin-2, (aldesleukin), has demonstrated to be an effective pharmacologic therapy for patients with advanced renal cell carcinoma. References: Rini, BI, Campbell SC, Escudier B. Renal cell carcinoma. The Lancet. 2009; 373(9669):1119-1132 Renal cell carcinoma First Aid 2014 page 216 ]]
Approved	Approved::Yes
Keyword	WBRKeyword::Renal cell carcinoma, WBRKeyword::Kidney cancer, WBRKeyword::Cancer, WBRKeyword::Renal cancer, WBRKeyword::Kidney, WBRKeyword::Chemotherapy, WBRKeyword::Interleukin, WBRKeyword::IL-2, WBRKeyword::Aldesleukin, WBRKeyword::Cancer immunology, WBRKeyword::Immunology, WBRKeyword::Immunotherapy, WBRKeyword::Cytokine
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