Neha Vapiwala, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 14, 2004
This is OncoLink's "It List" of targeted therapies – a sampling of the most promising targeted agents currently being developed and studied. Although these drugs are not yet FDA approved for clinical use, they are all actively under investigation, and thus represent the potential breakthrough "stars" of tomorrow.
SU11248 is an oral medication that appears to exert its antitumor antiangiogenic activity through targeting not only the vascular endothelial growth factor receptor (VEGFR), but also other pathways involved in the development of new blood vessels: platelet-derived growth factor receptor (PDGFR), KIT, and FLT3. A phase 1 study using SU11248 in 28 patients with solid tumors resulted in 6 tumor responses, based on before and after radiographic studies, with good tolerability of the drug. Another clinical trial looked at SU11248 in 32 patients with gastrointestinal stromal tumors (GIST) that failed to respond to imatinib (Gleevec) therapy. In this study, 11 of the 32 patients had either tumor shrinkage to some degree or durable stabilization of disease.
Given that this new agent is believed to work through more than one target, it is not easy to determine what the contribution is of each blocked pathway to achieving an antitumor effect. It is known, however, that patients' plasma levels of VEGF always increased after treatment with SU11248 in both of the above studies. One explanation for this is that the drug inhibits VEGF and leads to lowered oxygen supply from new blood vessels for the growing tumor. This in turn might prompt the tumor to overcome the problem by increasing production of VEGF. If this is indeed what occurs with SU11248 therapy, it would logically follow that maintaining patients on the drug is crucial, particularly during the period when tumor cells are trying to retaliate by revving up VEGF synthesis.
SU6668 is another oral, small molecule inhibitor of angiogenesis. This agent targets the following receptor subtypes tumor cells use to lay down new blood vessels: VEGFR-1, PDGFR-beta, and fibroblast growth factor receptor (FGFR-1). There are at least 4 different abstracts from phase 1 studies that have been reported, all showing minimal side effects. A phase 2 study to evaluate drug efficacy is in progress.
PTK787/ZK222584 is an oral angiogenesis inhibitor that specifically targets three subtypes of the VEGFR: VEGFR-1, VEGFR-2, and VEGFR-3. A phase 1 study looked at this agent in 43 patients with glioblastoma multiforme (GBM), an aggressive brain tumor with typically dismal prognosis. The treatment resulted in 1 partial response and 20 disease stabilizations. Even more impressive was the reduction in both blood vessel leakage (permeability) and blood volume in the brain one month after treatment, as compared to before treatment. This was measured using dynamic MRI scanning of the brain, and the effect on blood flow patterns seemed to correspond directly with the dose of drug.
Another phase-1 study specifically looking at dose-escalation and pharmacokinetics of PTK787/ZK222584 was first presented at ASCO 2001 and is ongoing. The treatment was found to be safe and tolerable. Stable disease was noted in 7 patients and disease progression in 5 patients. The authors measured blood-flow with ultrasound and dynamic MRI scans, and found that those patients with stable disease had a significantly greater reduction in tumor permeability and vascularity measurements than those who progressed.
Interestingly, this new agent is also being actively investigated as a possible treatment for rheumatoid arthritis.
CEP-7055 is a modified version of CEP-5214, an extremely potent small molecule inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3. Preclinical studies in lab mice by Ruggeri et al. for Cephalon, Inc. have shown that regular, twice-daily oral doses of CEP-7055 resulted in impressive stunting of tumor growth in nude mice implanted under the skin with cells from a variety of human cancers, including melanomas, glioblastomas, lung, breast, colon, pancreas and sarcomas. Also noted were reductions in growth of prostate and kidney tumor cells that were purposely injected into metastatic sites, such as the lungs. Clinically apparent responses were further confirmed under the microscope by findings of tumor cell death (apoptosis) and fewer blood vessels. The efficacy of the drug was not affected by extent of initial tumor volume, but did depend in continued administration of the drug. Taking the medication daily for period of up to 65 days appears to be safe with no serious side effects. Clinical phase 1 trials looking at twice-daily oral dosing are underway.
This novel agent represents a different approach from your typical targeted antiangiogenesis therapies. First of all, it is actually a lab-made enzyme, meaning it is a protein that breaks a specific substance down into smaller components. Secondly, rather than directly blocking the VEGF tumor cell receptor like the previously discussed targeted therapies, this drug works by blocking VEGF messenger RNA (mRNA); in other words, it is a RNA inhibitor, or "ribozyme".
RNA is a structure that is derived from a DNA template. Remember from high school biology that DNA is the genetic material we all inherit from our parents and which determines practically every aspect of our individual biology. RNA has three main subtypes, but here we will focus on mRNA. As its name implies, mRNA serves as a messenger, carrying the code that will later be translated into a particular protein.
Angiozyme specifically targets and cuts off part of the "code" that is needed to make VEGFR-1. By interfering with VEGFR-1 synthesis in this way, angiozyme ultimately reduces the number of VEGF type 1 receptors that are made and thus reduces angiogenesis.
At the 2003 ASCO meeting, results from a phase 2 trial of Angiozyme were presented. The drug was tested in 83 patients with colorectal cancer and no history of prior chemotherapy exposure. It was given together with the IFL chemotherapy regimen (irinotecan, 5-fluorouracil, and leucovorin), considered to be standard for colorectal cancer. A 43% tumor response rate was noted.
Mar 2, 2015 - Targeting a cancer cell's heat shock response protein 70 with panobinostat to induce autophagy in the stressed cell, and then introducing an autophagy inhibitor to force the cell to die off, may be an effective novel treatment strategy for breast cancer, according to a Nov. 16 press briefing presented at the American Association for Cancer Research -- National Cancer Institute -- European Organisation for Research and Treatment of Cancer International Conference, "Molecular Targets and Cancer Therapeutics," held from Nov. 15 to 19 in Boston.
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