Innovative Molecular Cancer Therapies

Debi Walker, ND
Lidia Dounaevskaia, ND

The art and science of oncology has been around for centuries. Egyptians documented characteristics and survival of women with breast tumors, and the oldest tumor registry dates back to 300-1500BC. Hippocrates coined the terms “benign” and “malignant” and used a classification system to predict survival. In the second century, cancer was believed to be incurable. In the 19^th century, the application of anesthesiology allowed for curative surgical resection of tumors in some patients. In the 20^th century, technological advances in molecular, chemical and cellular research resulted in the development of conventional chemotherapeutic agents, including antimetabolites, alkylating agents, anthracyclines and taxanes. Many of these agents target DNA synthesis and division, resulting in growth inhibition and tumor cell death.

Recent advances in our understanding of molecular processes involved in oncogenesis have created the foundation for a new era of molecular therapies that do not target DNA directly. Six such processes shared by nearly all malignant cells were identified:

• Self-sufficiency in growth signals
• Insensitivity to growth-inhibitory signals
• Evasion of programmed cell death (apoptosis)
• Limitless replicative potential
• Sustained angiogenesis
• Tissue invasion and metastasis (Adi and Kuniharu, 2004).

The focus of this review is on a few novel anti-cancer agents that are being directed at these exact processes, altering oncogene protein production, transduction pathways, angiogenesis and metastatic invasion.

Receptor Tyrosine Kinases

A superfamily of transmembrane proteins called receptor tyrosine kinases (RTKs) has been extensively researched as a target for molecular antineoplastic agents. The structure of these transmembrane receptor protein kinases is highly conserved. There is an extracellular ligand-binding domain, a transmembrane domain and an intracellular domain with tyrosine kinase activity. It has been well established that activation of these RTKs via ligand binding or receptor dimerization results in a cascade of phosphorylation of intracellular signaling molecules. Subsequently, the cellular response to RTK activation is proliferation, cell migration and stimulation of angiogenesis. Activation or overexpression of specific RTKs has been associated with many different cancers and can in some cases point to a more clinically aggressive cancer type. This activation and overexpression is tightly regulated in normal tissue.

Currently, there is a major effort to develop novel anticancer agents that specifically target RTKs. Two groups of drugs that currently show promising clinical efficacy are monoclonal antibodies, which inhibit binding of ligand to the extracellular domain of RTKs, preventing activation of the receptors; and tyrosine kinase inhibitors, which inhibit intracellular kinase activity of the receptor. Two RTK families that serve as the primary targets for these novel anticancer agents are the epidermal growth factor receptor (EGFR) family, and the vascular endothelial growth factor receptor (VEGFR) family.

EGFR

The human epidermal receptor family (HER) is a large subfamily of the EGFR tyrosine kinase family. The HER subfamily consists of four structurally similar transmembrane proteins: HER1 (EGFR or c-erbB1), HER2 (c-erbB2 and HER2/neu), HER3 (c-erB3) and HER4 (c-erB4). From a clinical relevance standpoint, we will discuss the most frequently used agents that target HER1 or HER2 subtypes.

HER1 Receptor Targets

EGFR (HER1, c-erbB1) is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle cells. In addition, a number of carcinomas, including non-small-cell lung cancer, head and neck cancer, pancreatic cancer and more than 70% of colorectal cancers have been found to overexpress EGFR (HER1, c-erbB1). Following is a brief review of agents that have been developed to target the HER1 (EGFR, c-erbB1) receptor.

• Cetuximab – Monoclonal Antibody. Cetuximab is a monoclonal antibody that specifically binds to the extracellular domain of EGFR (HER1, c-erbB1) and inhibits tyrosine kinase autophosphorylation (Tannook et al., 2005). Recent clinical trials showed marked improvement in locoregional control as well as overall survival when cetuximab was used in combination with radiation therapy in patients with squamous cell carcinoma of the head and neck. It also increased time to progression when used in combination with the chemotherapeutic agent irinotecan for patients with colorectal cancer (Kufe et al., 2006). Research has found that patients with tumors that are immunohistochemically negative for EGFR expression may still respond favorably to cetuximab, clearly indicating that this drug is capable of generating clinical responses against tumors expressing different surface antigens. Common side effects may include an acneiform rash, predominantly on the face and upper torso, fatigue and generalized malaise or lethargy (cetuximab package insert, 2006).
• Panitumumab – Human Monoclonal Antibody. Panitumumab is the most recently approved monoclonal antibody that also inhibits tyrosine kinase autophosphorylation through binding the extracellular domain of EGFR (HER1, c-erbB1). Clinical studies that compared best supportive care with or without panitumumab in patients with metastatic colorectal cancers showed significantly improved progression-free survival and disease control in the panitumumab group. Common side effects include acneiform rash, skin exfoliation and other dermatological toxicities, as well as injury of the gastrointestinal mucosa, causing diarrhea, especially when used concomitantly with irinotecan chemotherapy (Garny et al., 2006).
• Gefitinib – Tyrosine Kinase Inhibitor. Gefitinib was initially approved for metastatic non-small-cell lung cancer as a third-line therapy based on the results of Phase II studies (gefitinib package insert, 2005). Unfortunately, follow-up Phase III studies failed to demonstrate an increase in tumor response, time to progression or overall survival, resulting in restriction of its use by the FDA (Garny et al., 2006; US FDA, n.d.).
• Erlotinib – Tyrosine Kinase Inhibitor. Erlotinib is an oral agent that targets the intracellular tyrosine kinase domain of EGFR (HER1, c-erbB1) and was initially approved for metastatic non-small-cell lung cancer patients who had failed previous treatment. Erlotinib was proven to be effective in this patient population, showing an overall increase in survival and disease response rates (Shepherd et al., 2005). It showed higher efficacy among lifetime non-smokers, women and Asians. Currently, erlotinib is also used as a first-line therapy in combination with gemcitabine in patients with locally advanced, unresectable or metastatic pancreatic cancer (Moore et al., 2005). Common side effects include diarrhea and acneiform skin rash involving the face and upper trunk (Polovich et al., 2005). Other toxicities might include nausea, vomiting, elevated bilirubin, headaches and mucositis. Erlotinib is metabolized in the liver via the CYP450 family of enzymes; as such, caution should be exercised when using other agents with similar metabolism (erlotinib package insert, 2005).
• Imatinib – Non-RTK Inhibitor. Imatinib is a non-RTK inhibitor, which enables it to inhibit multiple tyrosine kinases. It works by inhibiting the bcr-abl tyrosine kinase, created by the abnormal Philadelphia chromosome in chronic myeloid leukemia (CML), resulting in a decrease in proliferation and induction of apoptosis. It is also more effective than other agents in inhibition of tyrosine kinase present in gastrointestinal stromal tumors (GIST). Common side effects include nausea, diarrhea, edema, dermatitis, muscle cramps, headache and gastrointestinal disturbances (imatinib package insert, 2006).

HER2 Receptor Targets

A number of carcinomas, including non-small-cell lung, acute lymphoblastic leukemia (ALL) and approximately 20%-30% of breast cancers, overexpress a tyrosine kinase growth factor receptor known as HER2/neu (c-erbB2). A definitive confirmation of HER2 overexpression is obtained with fluorescence in situ hybridization assay (FISH). Overexpression of HER2 has significant biological consequences, including increased tumor cell proliferation, invasion and metastasis, as well as increased angiogenesis and decreased tumor cell death. HER2/neu positive breast tumors are generally more aggressive and are associated with increased resistance to various chemotherapeutic agents and poor prognosis (Chevallier, 2004; Tokunaga, 2006). The following two agents target the HER2 receptor.

• Trastuzumab. Trastuzumab is a recombinant DNA-derived monoclonal antibody that targets the extracellular domain of HER2/neu. This results in inhibition of cell proliferation, invasion and metastasis, and increases the susceptibility of HER2/neu positive tumor cells to chemotherapy. Recent clinical trials demonstrated clear advantage with longer time to disease progression, higher response to treatment and longer survival in patients treated with trastuzumab in conjunction with conventional chemotherapeutics (Smith et al., 2007). Trastuzumab is administered either weekly or every three weeks and is usually well tolerated. In combination with doxorubicin or paclitaxel, increased cardiotoxicity has been observed (Tannook et al., 2005).
• Lapatinib. Lapatinib is a unique monoclonal antibody that targets both HER1 and HER2 subtypes of EGFR. It is still under investigation and is only available in clinical trials for patients with breast cancer who have failed trastuzumab therapy. A recent Phase III study showed that in combination with capecitabine, patients who received lapatinib had longer time to disease progression and fewer developments of brain metastasis (Geyer et al., 2006).

VEGFR

VEGFR represents another subfamily of the RTK superfamily. The activation of VEGFRs results in angiogenesis. This process is normally present in embryological development, tissues of the female reproductive system and healing. The angiogenic process is tightly regulated by the production and destruction of numerous angiogenic growth factors. The angiogenic growth factors are a diverse group of signaling molecules collectively referred to as vascular endothelial growth factors (VEGFs). Cells are stimulated to secrete VEGFs when stressed by hypoxic conditions or nitric oxide, and in the presence of other stimulating growth factors, such as epithelial growth factor (EGF) or insulin-like growth factor (IGF.) Tissues that respond to these stimulating growth factors include endothelial cells expressing VEGFR1 and VEGFR2 subtypes, and lymphatic vessels that express a third receptor subtype VEGFR3.

The oncogenic-driven production of growth factors orchestrates neovascularization from adjacent blood vessels to equip tumors larger than 1-2mm in diameter for progressive growth. Numerous molecular inhibitors of this process have been identified and have been shown to act either by directly blocking VEGFR signaling or by indirectly blocking the production of growth factors. Three VEGFR targeting agents have been developed and are showing good clinical efficacy:

• Bevacizumab. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody developed against VEGF that effectively blocks VEGF binding to its receptor, thus inhibiting neovascularization of tumor tissue. It is currently used as first- and second-line treatment in five fluorouracil-based chemotherapy regimens for metastatic colorectal carcinoma, demonstrating a higher response rate, longer time to tumor progression and prolonged overall survival (Iqbal et al., 2004). It is also beneficial for use in advanced non-small-cell lung cancer, metastatic breast cancer, renal cell carcinoma and recurrent ovarian carcinoma (Lyseng-Williamson et al., 2006). Bevacizumab is associated with a distinct array of toxicities, due to inhibition of multiple signaling pathways blocking angiogenesis (Herbst et al., 2006). The most serious complications reported include GI perforation, wound healing complication, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephritic syndrome and congestive heart failure. It has been recommended that bevacizumab not be initiated for at least 28+ days following surgery, with tissue healing complete. The appropriate interval between termination of bevacizumab and subsequent elective surgery to avoid the risks of impaired wound healing/wound dehiscence has not been determined. The half-life for bevacizumab is long (average T1/2 is 20 days; range 11-50 days) and should be considered in these situations (Avastin, n.d.).
• Sorafenib. Sorafenib is an orally available tyrosine kinase inhibitor that targets multiple receptor kinases involved in angiogenesis (Flaherty, 2007). In vitro studies have shown that sorafenib caused decreased endothelial cell proliferation and increased both endothelial cell and tumor cell apoptosis. Sorafenib was approved for treatment of patients with advanced renal cell carcinoma (National Cancer Institute, n.d.). Common side effects include diarrhea, rash, fatigue, hand-foot skin reactions, alopecia and nausea. Hypertension and cardiac ischemia and infarction were observed in rare cases (Escudier, 2007). As with other anti-angiogenesis agents, sorafenib should be discontinued prior to surgery and not initiated until wound healing has completed (Nexavar package insert online, n.d.).
• Sunitinib. Sunitinib is another anti-angiogenesis agent that serves as a multiple RTK inhibitor. It was approved for treatment of GIST in patients with disease progression on imatinib or intolerance to imatinib, and for treatment of advanced renal cell carcinoma. Sunitinib was approved by the U.S. Food and Drug Administration through the accelerated process used for drugs considered to have demonstrated the potential to save or extend lives in cases of serious disease (U.S. FDA, n.d.). Further clinical trials regarding the clinical applications of the drug will be completed in the post-market environment. It is important that clinicians closely monitor patients and get frequent updates regarding new information about the drug as it is released. Common side effects from sunitinib therapy include fatigue, nausea/vomiting, abdominal pain, mucositis/stomatitis, skin discoloration, altered taste sense and anorexia (Cerner Multum, n.d.). Other adverse effects noted included hypothyroidism, neutropenia, thrombocytopenia and in rare instances pancreatitis. Cardiovascular toxicity has been noted to occur with a decrease in left ventricular ejection fraction. Rare yet life-threatening tumor-related hemorrhages have also occurred with this therapy (National Cancer Institute, n.d.).

Many scientists and healthcare providers believe that molecular therapies are the chemotherapy of the future. Researchers continue to identify and evaluate molecular targets that are potential candidates for new drug development. Currently, more than 150 companies are involved in the research and development of 260 novel agents against 45 different cancer types. The art and science of future oncology will be highly individualized based on the unique set of molecular targets produced by each patient’s tumor. This will allow treatment to be less toxic, more specific and vastly more effective at improving the quality of life and survival of patients with cancer. It is also our hope that more research will be done to identify natural therapies that will further reduce side effects, and increase specificity and effectiveness of these novel anticancer therapies.

Debi Walker, ND received her undergraduate degree in physiology/cell biology from Universtiy of California at Santa Barbara and completed her doctorate in naturopathic medicine at Bastyr University in 2006. She is currently participating in a residency program specializing in naturopathic oncology at Cancer Treatment Centers of America in Zion, Ill.

Lidia Dounaevskaia, ND received her undergraduate degree in biology from Rutgers University and graduated with a naturopathic medicine degree from NCNM in 2003. She completed a two-year residency specializing in naturopathic oncology at Cancer Treatment Centers of America in Zion, Ill. In 2005, she joined the staff of naturopathic doctors at CTCA and continues to provide naturopathic care to patients diagnosed with cancer.

References

1. Adi FG, Kuniharu M: Molecular targets for cancer therapy and prevention, CHEST 125:97S–101S, 2004.
2. Tannook et al: The Basic Science of Oncology. New York, 2005, The McGraw-Hill Companies.
3. Kufe et al: Cancer Medicine, ed 7, Hamilton, Ontario, 2006 BC Decker American Association for Cancer Research.
4. Garny P et al: Understanding Novel Molecular Therapies. Nashville, Nov 2006, Vanderbilt-Ingram Cancer Center.
5. Iressa (Gefitinib) tablets, package insert. Wilmington, June 2005, AstraZeneca Pharmaceuticals.
6. US Food and Drug Administration: Safety alerts for drugs, biologics, medical devices and dietary supplements. http:fda.gov/cder/drug/infopage/gefitinib/default.htm
7. Tarceva (erlotinib) tablets, package insert. San Francisco, Nov 2005, Genentech.
8. Shepherd FA et al: Erlotinib in previously treated non-small-cell lung cancer, N Engl J Med 353:123-132, 2005.
9. Moore MJ et al: Erlotinib improves survival when added to gemcitabine in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. ASCO Gastrointestinal Cancers Symposium 2005; Abstract 77 as cited in Cohenuram et al: Epidermal growth factor receptor inhibition strategies in pancreatic cancer: past, present and the future JOP, Journal of the Pancreas January (8)1, 2007.
10. Polovich M et al: Chemotherapy and Biotherapy Guidelines and Recommendations for Practice ed 2, Pittsburgh, 2005, Oncology Nursing Society.
11. Gleevec (imatinib) tablets, package insert. East Hanover, Nov 2006, Novartis.
12. Chevallier P et al: Overexpression of Her2/neu is observed in one-third of adult acute lymphoblastic leukemia patients and is associated with chemoresistance in these patients, Haematologica Nov:89(11):1399-401, 2004.
13. Tokunaga E et al: Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients, Int J Cancer Jan 15:118(2):284-9, 2006.
14. Smith I et al: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomized controlled trial, Lancet Jan 6;369(9555):29-36, 2007.
15. Geyer CE et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer, N Engl J Med Dec 28;355(26):2733-43, 2006.
16. Iqbal S, Lenz HJ et al: Integration of novel agents in the treatment of colorectal cancer, Cancer Chemother Pharmacol Sep; 54 Suppl 1:S32-9, 2004.
17. Lyseng-Williamson KA et al: Spotlight on bevacizumab in advanced colorectal cancer, breast cancer, and non-small cell lung cancer, BioDrugs 20(3):193-5, 2006.
18. Herbst RS: Toxicities of antiangiogenic therapy in non-small-cell lung cancer, Clin Lung Cancer Dec; 8 Suppl 1:S23-30, 2006.
19. Avastin: www.avastin.com/avastin/resources/avastinFAQForNurses.pdf
20. Flaherty KT: Sorafenib in renal cell carcinoma, Clin Cancer Res Jan 15;13(2):747s-52s, 2007.
21. National Cancer Institute: www.cancer.gov/cancertopics/druginfo/fda-sorafenib-tosylate
22. Escudier B et al: Sorafenib in advanced clear-cell renal-cell carcinoma, N Engl J MedJan 11;356(2):125-34, 2007. As cited in Chustecka Z: Sunitinib and Sorafenib confirm efficacy in renal cell carcinoma, Medscape Medical News 2007.
23. Nexavar package insert online: www.univgraph.com/bayer/inserts/nexavar.pdf
24. U.S. Food and Drug Administration. FDA news: FDA approves new treatment for gastrointestinal and kidney cancer: www.fda.gov/bbs/topics/news/2006/NEW01302.html
25. Cerner Multum: www.multum.com/sunitinib.htm
26. National Cancer Institute: www.cancer.gov/cancertopics/druginfo/fda-sunitinib-malate.
27. Erbitux (cetuximab) package insert. Princeton, March 2006, Bristol-Myers Squibb Company.