Angiogenesis inhibitors
Angiogenesis inhibitors are a class of drugs designed to block the formation of new blood vessels, a process known as angiogenesis. This mechanism is particularly important in cancer treatment, as tumors rely on a steady blood supply to grow and metastasize. By inhibiting angiogenesis, these medications aim to starve tumors of the necessary oxygen and nutrients, potentially leading to slower tumor growth or even shrinkage. Approved by the FDA for various cancer types, including multiple myeloma, metastatic colorectal cancer, and advanced renal cancer, some notable angiogenesis inhibitors include Velcade, Avastin, Nexavar, and Thalomid.
These drugs can be administered in different forms, including intravenously, subcutaneously, or orally. The efficacy of angiogenesis inhibitors has been observed to improve when they are used in combination with other cancer treatments, underscoring their potential as a vital part of a comprehensive cancer therapy regimen. However, patients may experience a range of side effects depending on the specific medication, highlighting the importance of careful management during treatment. As clinical research continues, the role of angiogenesis inhibitors in oncology remains a significant area of study.
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Angiogenesis inhibitors
DEFINITION: Angiogenesis inhibitors prevent the formation of new blood capillaries through a process called angiogenesis, as a result of which cancer tumors are starved and die.
Cancers treated:Multiple myeloma, mantle cell lymphoma, metastatic colorectal cancer, advanced renal cancer, gastrointestinal stromal tumors
Delivery routes: Delivered intravenously (Avastin, Velcade) or subcutaneously (Velcade) on an inpatient basis or orally in tablet (Nexavar, Afinitor, Votrient) and capsule (Sutent, Thalomid) forms on an at-home basis
How these drugs work: Angiogenesis is critical to normal growth, providing a network of new blood capillaries that deliver oxygen and nutrients to developing tissues. Once formed, capillaries do not increase in size or number, because the endothelial cells that line them do not divide. In some normal conditions (wound repair, menstruation), however, they do.
Tumors require a constant supply of newly formed blood capillaries in order to grow. Early in the angiogenesis process, tumors secrete growth factors, which signal the endothelial cells to proliferate. The new capillaries attach themselves to the tumor and deliver oxygen and nutrients. This blood supply also allows tumor cells to spread to other areas of the body (metastasize), a process that is a major cause of cancer deaths.
Some scientists have long hypothesized that attacking angiogenesis might be a powerful tool in preventing tumor growth. Removing the blood supply might prevent the growth of new tumor cells and cause the tumors to grow more slowly or become smaller. In 1971, Dr. Judah Folkman, of Children’s Hospital in Boston, published a paper proposing that all tumor growth is angiogenesis dependent. This founded the field of angiogenesis research and control, a field of investigation that is now studied by many scientists.
By 2014, the US Food and Drug Administration (FDA) had approved several angiogenesis inhibitors for use in cancer treatment, including bortezomib (trade name Velcade), bevacizumab (Avastin), sorafenib tosylate (Nexavar), sunitinib malate (Sutent), thalidomide (Thalomid), everolimus (Afinitor), and pazopanib hydrochloride (Votrient).
Velcade was approved in 2003 for the treatment of multiple myeloma patients who had received at least two prior therapies with anticancer drugs and had demonstrated disease progression on the last therapy. It was approved in 2005 for multiple myeloma patients who had received one prior therapy and in 2006 for mantle cell in patients who had received one prior therapy. Velcade interrupts various cell-signaling pathways critical to angiogenesis.
Avastin was approved in 2004 to treat metastatic colorectal cancer. It is believed to act by attaching to a protein growth factor active in angiogenesis. When the growth factor is bound to Avastin, it cannot carry out its function in the angiogenesis process. Avastin enhances the effects of standard chemotherapy but does not appear to be effective when given alone to patients with colorectal cancer.
Nexavar was approved in 2005 to treat adults with advanced renal cell carcinoma, an aggressive form of the disease and the most common of kidney cancers. In 2007 it was approved to treat hepatocellular carcinoma, the most common type of liver cancer, as well. Nexavar is a small molecule, and as such, it enters endothelial cells and inhibits enzymes involved in intercellular signaling linked to cell division; it also acts by binding to vascular endothelial growth factor (VEGF).
Sutent was approved in 2006 for the treatment of gastrointestinal stromal tumors and advanced kidney cancer. Sutent is also a small molecule that enters tumor cells and prevents angiogenesis and cell proliferation by blocking the signaling activity of several growth factors.
Thalomid (thalidomide) was approved in 2006 for the treatment of newly diagnosed multiple myeloma, in combination with the chemotherapy drug dexamethasone. Thalidomide’s activity depends on its ability to block the growth factor signals necessary for angiogenesis. In 1994, Folkman and coworkers published a paper providing evidence that thalidomide is an angiogenesis inhibitor. Its ability to block the development of new blood vessels likely caused the limb malformations in babies of mothers who took the drug as a sedative during pregnancy. Both men and women taking the drug for cancer treatment are required to use contraception to avoid pregnancy.
Afinitor was approved in 2009 for the treatment of advanced renal cell carcinoma in patients who had failed to respond to Nexavar or Sutent. It was subsequently also approved for subependymal giant cell astrocytoma (SEGA) with associated tuberous sclerosis (2010), progressive neuroendocrine tumors of pancreatic origin (PNET) that have locally advanced or metastasized (2011), and renal angiomyolipoma with tuberous sclerosis (2012). Afinitor works by inhibiting mechanistic target of rapamycin (mTOR), a serine/threonine protein kinase that regulates cell growth, as well as by reducing VEGF expression.
Votrient was approved in 2009 to treat advanced renal cell carcinoma. In 2012 it was approved for treatment of advanced soft-tissue sarcoma in patients who have already received chemotherapy. Votrient is a tyrosine kinase inhibitor that inhibits various growth-factor receptors, including VEGF receptors (VEGFR-1, VEGFR-2, and VEGFR-3), platelet-derived growth factor receptors (PDGFR-α and PDGFR-β), and fibroblast growth factor receptors (FGFR-1 and FGFR-3), among others.
In the mid-2020s, clinical trials began that studied the effects angiogenesis inhibitors had against various types of cancers. These studies also sought data on side effects and whether the efficacy of angiogenesis inhibitors could be increased by combining them with other treatments. By 2021, clear patterns had emerged that showed that angiogenesis inhibitors were effective against advanced cancers. This method was particularly evident when compared to treatments where angiogenesis inhibitors were not administered. Angiogenesis inhibitors also showed great promise when used in combination with other treatments.
By 2022, the FDA had given its approval to fifteen angiogenesis inhibitors.
Side effects: The side effects of angiogenesis inhibitors depend on the medication. Some of the more common angiogenesis inhibitors have the following side effects:
- Velcade: Fatigue, nausea, diarrhea, anorexia, constipation, thrombocytopenia, peripheral neuropathy, pyrexia, vomiting, and anemia
- Avastin: High blood pressure, fatigue, blood clots, diarrhea, decreased white blood cells, headache, appetite loss, and mouth sores
- Nexavar: Rash; diarrhea; high blood pressure; redness, pain, swelling, or blisters on the palms of the hands or soles of the feet
- Sutent: Diarrhea, skin discoloration, mouth irritation, weakness, altered taste, fatigue, high blood pressure, bleeding, swelling, and hypothyroidism
- Thalomid: Somnolence, constipation, neuropathy, venous thromboembolism, and rash
- Afinitor: Stomatitis, infections, rash, fatigue, diarrhea, decreased appetite, nausea, weight loss, cough, altered taste, dyspnea, headache, arthralgia, peripheral edema, vomiting, pyrexia, constipation, hyperglycemia, back pain, weakness
- Votrient: Diarrhea, hypertension, changes in hair color, nausea, anorexia, vomiting, fatigue, weakness, abdominal pain, headache
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