Biomedical subjects

W Kimryn Rathmell

Publications and source records attributed to W Kimryn Rathmell.

8 recordsLinked to original sources

PubMed2006

Renal cell carcinoma.

PURPOSE OF REVIEW: In this review we will highlight the recent novel contributions to the treatment of renal cell carcinoma in the fields of anti-angiogenesis, immunotherapeutics, and surgical management. In addition, this review will update recent advances in diagnostic and imaging modalities for renal cell carcinoma and dietary and environmental relationships to the epidemiology of this growing disease. RECENT FINDINGS: Advancements in the use of innovative treatment strategies for the management of localized renal cell carcinoma and the introduction of new targeted therapeutics with benefit in the metastatic setting has produced a major impact on the treatment of this disease. SUMMARY: The management of metastatic renal cell carcinoma has undergone a revolution in the past year with groundbreaking treatment strategies encompassing a broad range of therapeutic modalities. At the other end of the spectrum, emerging data is beginning to change our perspective about the management of small, localized renal tumors that are being discovered with increasing frequency. This review will update recent findings supporting diet and tobacco exposure as etiologic factors in the development of renal cell carcinoma, the molecular concepts that underlie the disease and the targeted therapeutics designed to inhibit specific kinase activities, and emerging use of minimally invasive therapies for localized disease.

Angiogenesis Inhibitors↗

PubMed2005

Renal cell carcinoma.

PURPOSE OF REVIEW: This review focuses on recent developments in the biology and clinical therapeutics of renal cell carcinoma. Given historically limited advances in this disease, a more thorough understanding and testing of rationally targeted agents is needed. RECENT FINDINGS: Von Hippel-Lindau gene inactivation is observed in most clear cell renal carcinoma, driving the malignant phenotype. The resulting vascular endothelial growth factor overexpression has been targeted though various approaches, with a clear signal of anti-tumor activity. In addition, immunotherapy remains a therapeutic standard in renal cell carcinoma and an area of ongoing investigation. Observation of small renal masses may represent a viable clinical option. SUMMARY: Renal cell carcinoma has become a model disease for rationally targeted therapeutics based on significant understanding of the underlying biology. Recent advances have increased the potential for meaningful improvements in clinical outcomes for renal cell carcinoma patients.

Angiogenesis Inhibitors↗

PubMed2005

Molecularly targeted therapy in renal cell carcinoma.

Recent developments in the molecular biology of renal cell carcinoma have identified multiple pathways associated with the development of this cancer. Multiple strategies have been investigated targeting these pathways, with significant clinical benefits shown in early studies. This review aims to overview the findings of recent clinical trials and clarify the development of these compounds for use in renal cell carcinoma. The authors also aim to clarify the molecular pathways implicated in renal cell carcinoma and the clinical results in metastatic renal cell carcinoma with agents targeting these pathways. The relevant literature was reviewed concerning pathways implicated in the pathophysiology of renal cell carcinoma including pathways activated secondary to von Hippel-Lindau gene inactivation and PI-3 kinase/Akt/mammalian target of rapamycin pathway activation. Therapeutic targeting based upon underlying molecular biology in renal cell carcinoma has strong rationale. Substantial clinical activity has been reported with various agents targeting these pathways, most notably with vascular endothelial growth factor-targeted therapy. However, investigation is needed to optimally utilize these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.

Animals↗

PubMed2004

In vitro and in vivo models analyzing von Hippel-Lindau disease-specific mutations.

Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene cause tissue-specific tumors, with a striking genotype-phenotype correlation. Loss of VHL expression predisposes to hemangioblastoma and clear cell renal cell carcinoma, whereas specific point mutations predispose to pheochromocytoma, polycythemia, or combinations of hemangioblastoma, renal cell carcinoma, and/or pheochromocytoma. The VHL protein (pVHL) has been implicated in many cellular activities including the hypoxia response, cell cycle arrest, apoptosis, and extracellular matrix remodeling. We have expressed missense pVHL mutations in Vhl(-/-) murine embryonic stem cells to test genotype-phenotype correlations in euploid cells. We first examined the ability of mutant pVHL to direct degradation of the hypoxia inducible factor (HIF) subunits HIF1alpha and HIF2alpha. All mutant pVHL proteins restored proper hypoxic regulation of HIF1alpha, although one VHL mutation (VHL(R167Q)) displayed impaired binding to Elongin C. This mutation also failed to restore HIF2alpha regulation. In separate assays, these embryonic stem cells were used to generate teratomas in immunocompromised mice, allowing independent assessment of the effects of specific VHL mutations on tumor growth. Surprisingly, teratomas expressing the VHL(Y112H) mutant protein displayed a growth disadvantage, despite restoring HIFalpha regulation. Finally, we observed increased microvessel density in teratomas derived from Vhl(-/-) as well as VHL(Y112H), VHL(R167Q), and VHL(R200W) embryonic stem cells. Together, these observations support the hypothesis that pVHL plays multiple roles in the cell, and that these activities can be separated via discrete VHL point mutations. The ability to dissect specific VHL functions with missense mutations in a euploid model offers a novel opportunity to elucidate the activities of VHL as a tumor suppressor.

Animals↗

PubMed2004

Renal cell carcinoma.

PURPOSE OF REVIEW: Renal cell carcinoma continues to be a devastating cancer, which currently has few effective treatment options. Recent developments in our understanding of the molecular biology of renal cell carcinoma, particularly clear cell renal cell carcinoma, have led to the development of new agents targeting portions of the hypoxic response pathway. RECENT FINDINGS: Although high-dose bolus interleukin-2 remains the mainstay of treatment for metastatic disease, the number of patients deriving long-term benefit from this treatment are few, and the use of cytokine therapy in the adjuvant setting has been disappointing. However, the expanding use of minimally invasive surgical techniques has continued to improve patient care. Systemic advances include antibody therapeutics such as bevacizumab, which targets vascular endothelial growth factor signaling, as well as emerging small molecule inhibitors of angiogenesis-related signaling events. SUMMARY: In addition to progress in surgical techniques and supportive care of patients with renal cell carcinoma, a host of promising targeted therapies for renal cell carcinoma are on the horizon.

Carcinoma, Renal Cell↗

PubMed2004

Phase II trial of 5-fluorouracil and leucovorin in combination with interferon-alpha and interleukin-2 for advanced renal cell cancer.

Recent clinical trials have demonstrated activity of chemoimmunotherapy with interleukin-2 (IL-2), interferon-[alpha], and 5-fluorouracil (5-FU) in advanced renal cell cancer. A phase II study was performed to evaluate the affect of adding the potentiating agent leucovorin to this combination regimen. Treatment courses consisted of IL-2 5 MIU/m2 subcutaneously days 1, 3, and 5 of weeks 1 to 4, interferon-[alpha] 3 MIU/m2 subcutaneously on days 1, 3, and 5 of weeks 1 to 4, and leucovorin 50 mg/m2 IV followed by 5-FU 450 mg/m2 IV infusion weekly weeks 1 to 4. Patients were given no treatment on weeks 5 and 6 of the 6-week treatment cycle. Of the 20 patients enrolled in the study, 16 were evaluable for toxicity and 15 were evaluable for tumor response. The most severe toxicities included three reports of grade IV diarrhea; overall, nine incidents of grade III or IV toxicity were reported. No objective antitumor responses were observed, and the median time to progression was 2.8 months. We conclude that this combination chemoimmunotherapy regimen has substantial toxicity but no significant antitumor activity in patients with advanced stage renal cell carcinoma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth.

Inactivation of the von Hippel-Lindau (VHL) gene is associated with the development of highly vascularized tumors. pVHL targets the alpha subunits of hypoxia inducible factor (HIF) for ubiquitin-mediated degradation in an oxygen-dependent manner. Although pVHL-deficient tumor cell lines demonstrate constitutive stabilization and activation of HIF, it has yet to be shown that loss of murine Vhl alone is sufficient to dysregulate HIF. We utilized a genetic approach to demonstrate that loss of Vhl is sufficient not only to stabilize HIF-alpha subunits under normoxia, but also fully activate HIF-mediated responses. These studies have implications for the hierarchy of signaling events leading to HIF stabilization, nuclear translocation, and target gene expression. We further demonstrate that loss of murine Vhl does not promote teratocarcinoma growth, indicating that other genetic changes must occur to facilitate Vhl-mediated tumorigenesis.

Animals↗

PubMedDate not supplied

HIF transcription factor expression and induction of hypoxic response genes in a retroperitoneal angiosarcoma.

Angiosarcoma is a rare and highly aggressive tumor of endothelial origin. The molecular mechanisms driving angiosarcoma growth have not been fully elucidated, although autocrine stimulation by vascular endothelial growth factor (VEGF) secretion may play a role in the pathogenesis of this tumor. We identified a patient with a very rare form of angiosarcoma arising from the retroperitoneum. Immunohistochemical analysis demonstrated widespread up-regulation of the hypoxic response pathway as a mechanism of enhanced VEGF expression. Disordered regulation of the hypoxic response pathway can result in the expression of factors such as VEGF and erythropoietin, which may promote autocrine tumor growth in angiosarcoma.

Basic Helix-Loop-Helix Proteins↗