A natural liquid cartilage extract brings new hope for patients with metastatic renal cell carcinoma

Townsend Letter for Doctors and Patients,  Jan, 2004  by Dominique Garrel

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Abstract

The latest progress and trends in antiangiogenic therapy were recently presented at the "Angiogenesis: New Opportunities & Solutions for Drug Development" meeting held on September 29-30, 2003 in Cambridge, Massachusetts. The conference featured Dr. Judah Folkman, MD, a pioneer in angiogenesis research, as keynote speaker. Biopharmaceutical leaders in the field also presented their latest reports of ongoing clinical trials. Much awaited by all attendees, were the results of a recently completed Phase III trial of a natural liquid cartilage extract (LCE) as monotherapy for stage IV metastatic renal cell carcinoma (RCC) refractory to conventional treatments. Patients enrolled in the study were stratified into four groups, according to their ECOG status (0 or 1) and the number of metastatic sites (1 or more than 1). Results from this placebo controlled, double-blind clinical trial revealed a significant survival advantage for a cohort of patients with clear cell histology, an ECOG=0, and a single metastatic site. For this preplanned group of 38 patients, oral administration of LCE more than doubled life expectancy, 26.3 months for LCE compared to 12.6 months for placebo, with a convincing p value= 0.02. For the first time ever, a group of patients with metastatic RCC refractory to the standard treatment, showed statistically significant clinical benefits with a natural product. Once again LCE confirmed its outstanding safety profile. LCE's success in such harsh conditions augurs well for its use in first line combination therapies.

Angiogenesis and tumor growth

Angiogenesis is the process through which new blood vessels form and grow. Angiogenesis is a natural physiological function which can be subverted by cancer cells to satisfy their increasing need for nutrients and oxygen as tumors grow untamed. The angiogenic process, as currently understood, can be summarized as follows: a cell activated by a lack of oxygen (or a mutation) releases, among other things, angiogenic factors that attract inflammatory and endothelial cells and promote their proliferation. In the course of their migration, inflammatory cells secrete additional substances that intensify the angiogenic call. The endothelial cells that form existing blood vessels respond to angiogenic signals in their vicinity by proliferating and secreting proteases, which break open the blood-vessel wall to enable them to migrate toward the site of the angiogenic stimuli. Proliferating endothelial cells then organize themselves into new capillary tubes by altering the arrangement of their adherence-membrane proteins. Finally, through the process of anastomosis, the capillaries emanating from the arterioles and the venules join to provide a continuous blood flow that sustains tumor cell metabolism and sets up escaping avenues for metastatic tumor cells (Fig. 1).

[FIGURE 1 OMITTED]

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Modulators of angiogenesis

A variety of different growth factors and cytokines can promote angiogenesis, but one of the most important is vascular endothelial growth factor (VEGF). VEGF is a soluble protein secreted by most types of cells, except by endothelial cells themselves. On the other hand, endothelial cells express receptors for this growth factor. Hypoxic conditions, as seen in cancer growth, are a potent trigger of VEGF expression. Interaction of VEGF with its receptor induces an intracellular signaling cascade that favors endothelial cell survival, proliferation and migration and increases vascular permeability. VEGF also up-regulates the expression of other proteins involved in angiogenesis. High serum levels of VEGF correlates with poor prognosis in cancer patients.

VEGF relies on the complementary action of matrix metalloproteinases (MMPs) for the process of angiogenesis. MMPs are key proteins in the extension of the vascular bed. MMPs form a family of structurally related, zinc-dependent endopeptidases secreted by various cell types, including endothelial cells. MMPs collectively have the potential to degrade all of the protein and proteoglycan components of the extracellular matrix (ECM) surrounding cells. MMPs also influence important cellular processes and immune cell functions through proteolytic processing and shedding of bioactive molecules such as cytokines and growth factors. In the context of tumor angiogenesis, MMPs digest the blood-vessel walls enabling endothelial cells to make their way toward the tumor and providing cancer cells with breaches through which they can spread to distant organs (Fig. 2).

Advanced Renal Cell Carcinoma

Although RCC ranks only seventh among other causes of cancer and accounts for less than 3% of all malignancies, it is a deadly disease, leaving very little hope for newly diagnosed patients. Estimations for 2003 predict the discovery of 31,000 new cases in the USA and a death toll of almost 11,900 patients. There are three main reasons for such a high death rate. First, RCC is a silent disease lacking early warning signs. By the time RCC patients seek for medical advice, nearly half of them harbor locally advanced (stage III) or metastatic disease (stage IV) (see Fig. 3). Second, even early-stage RCC, that can be treated with nephrectomy, tends to progress to metastatic disease within one year of surgery. Third, advanced RCC responds very poorly to chemotherapeutic treatment (less than 10% have a partial response) and not at all to radiotherapy. Chemoresistance has been linked to the presence of efflux pumps at the surface of RCC cells (Zhang et al, 2000). Immunomodulation with interferon-alpha (IFN) and/or interleukin-2 (IL-2) is the standard treatment for advanced RCC but is hampered with a limited response rate (less than 20%) and significant toxicity. Overall, the prognosis for metastatic RCC is quite somber, with a median survival time of 6 to 12 months and a five year survival rate of less than 5% (Flanigan et al, 2003).