National Institute of Dental and Craniofacial Research, Oral and Pharyngeal Cancer Branch
National Institutes of Health
AT van Oosterom
Professor and Chairman
Department of Oncology
The conventional approach to treating cancer generally includes surgery, radiotherapy and drug therapy (hormonal therapy and chemotherapy). The cure rate using chemotherapy is about 12% for all cancers but is restricted to a limited number of cancer types, including leukaemia, lymphomas, germ-cell tumours and certain sarcomas. For other types of cancer, conventional drug therapy induces only a temporary remission and sometimes does not work at all. Reasons for the failure to cure are:
- Initial or developed drug resistance.
- Poor penetration of the drug into the tumour.
- Poor specificity, leading to dose-limiting toxicities.
Recent progress in the understanding of the genetic and biochemical changes that occur in cancer cells is now contributing to the development of more specific anticancer therapies. Some promising molecules underwent clinical trials in the 1990s, although it is too early to predict the value of these new strategies in their clinical applications.
Deranged intracellular signalling caused by alterations in genes is a keystone in our modern understanding of cancer. Activation and overexpression of oncogenes, together with the loss of tumour suppressor genes, disturb the cells’ fine equilibrium and induce a continuous growth signal. Over 100 oncogenes have been identified. Alterations in these oncogenes influence several pathways leading to mitogenesis. Development of many new drugs is focused on different specific mechanisms in these pathways.
Conventional drug therapy
Tamoxifen remains the reference in the hormonal therapy of breast cancer. Some large trials are currently evaluating the role of tamoxifen in preventing breast cancer. In patients with a high risk for breast cancer (as defined by the Gail model), chemoprevention seems to be of value. A reduction in the incidence of breast cancer has been observed in one study of patients who received tamoxifen.(1) However, due to an early crossover in the study, it is impossible to find a survival benefit. Moreover, other trials were not able to confirm tamoxifen’s benefit in preventing cancer. This might be explained by the differences in the inclusion criteria.(2)
More selective analogues of tamoxifen have recently been developed. Raloxifene, a selective oestrogen receptor modulator, is one of these. This molecule has not yet been studied in the treatment of breast cancer. However, it is expected to have an oestrogenic effect on bones, the lipid profile and endometrial tissue. Although its effects in breast cancer have to be awaited, raloxifene is a valuable candidate for a comparative study with tamoxifen in the prevention of breast cancer.
The addition of steroidal antioestrogens (eg, faslodex) and steroidal aromatase inhibitors (eg, exemestane) to the gamma of non-steroidal antioestrogens and aromatase inhibitors allows prolonged disease-free survival in oestrogen receptor-positive breast cancer.
Chemotherapy progress in recent years has been in:
- The optimisation of existing potent cytostatic drugs.
- The discovery of analogues that are better absorbed and can be taken orally, making therapy more comfortable for patients.
- The development of some new drugs that show activity against tumours generally thought to be insensitive to chemotherapy.
- The exploration of new sources of drugs.
Doxorubicin provides an example of an existing cytostatic drug that has been optimised. The use of doxorubicin, which is one of the most potent known anticancer drugs, is restricted by its toxicity (eg, cardiac toxicity). However, the new liposomal doxorubicin, doxil, has very different pharmacokinetics from those of the usual form of doxorubicin. The liposomes remain in the circulation for a prolonged time and are only slowly eliminated by the reticuloendothelial system.
In phase I and II studies, doxil showed good haematological tolerance and caused only slight mucositis and palmoplantar dermatitis.(3) Moreover, its cardiac toxicity is much less than that of the usual form of doxorubicin. This makes doxil a promising drug for patients who have cardiac dysfunction and for elderly patients.
Capecitabine is an example of an improved analogue – it is a cytostatic analogue with better absorption. Capecitabine is a prodrug of 5-fluorouracil (5-FU) that is well absorbed and can be taken orally. It is metabolised in the liver. Capecitabine’s effectiveness in colon and breast cancer is comparable to that of a prolonged infusion with 5-FU.
Multitargeted antifolate (MTA) is a new drug that shows activity against tumours generally thought to be insensitive to chemotherapy. In combination with cisplatin it induced a partial response in four out of seven patients with mesothelioma. The results of larger trials are eagerly awaited.(4) Recently it was shown that the side-effects of MTA (eg, neutropenia, fatigue and skin toxicity) can be reduced by administration of vitamin supplements before and during the therapy. This strategy would probably reduce the toxicity of the folate-based thymidylate synthase inhibitor raltitrexed as well.
Cytostatic drugs are a good example of new sources of drugs. Many cytostatic drugs are derivatives of molecules found in plants or animals. Recently, a new alkaloid cytostatic drug has been discovered in the ocean – the molecule ET-743 – which is derived from the Caribbean tunicate Ecteinascidia turbinata. In preclinical models, it differs from the currently used alkaloids in its biochemical activities and in its antitumour profile. The precise antitumour activity mechanisms of ET743 have not yet been elucidated. However, the results of its effectiveness for patients with sarcomas in phase I and II clinical trials are very encouraging.
New anticancer drug development
1.Targeting the signalling pathways leading to mitogenesis
Growth factors – growth factors expressed in an unlimited way can cause an autocrine loop. The receptors of these growth factors are located at the surface of cells, making them vulnerable to specific monoclonal antibodies (Mabs). The erbB-2 (HER2/neu) receptor and epidermal growth-factor receptor (EGFR) are the most commonly chosen targets for Mab therapy. The former is overexpressed in 20–30% of patients with breast cancer.
Use of trastuzumab, the first humanised Mab directed against the HER2/neu receptor, results in a remission rate of 15% in resistant breast cancer. Therapy using trastuzumab in combination with conventional cytostatic drugs (eg, cisplatin, paclitaxel and anthracyclines) induces a higher response rate and a prolonged time to progression without major toxicity, apart from an unacceptable increase of cardiac toxicity when combined with anthracyclines.(5)
Rituximab is a chimeric Mab that is directed against CD20, which is overexpressed in follicular and other low-grade B-cell non-Hodgkin’s lymphoma. Phase II studies show a partial or complete remission with rituximab in about 50% of patients with intensively pretreated low-grade non-Hodgkin’s lymphoma.(6) The maximal response was between the first and the fourth months after treatment. Combination of rituximab with chemotherapy (eg, cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP] regimen) is safe, and the clinical responses are at least comparable to those achieved with CHOP alone.(7) However, if there are a large number of tumours, acute and even life-threatening intravascular tumourlysis can occur after infusion of rituximab.
Protein kinases – receptor tyrosine kinases (RTKs) and non-membrane-spanning cytoplasmic protein tyrosine kinases are important components of several signalling pathways leading to mitogenesis. They mediate the response of a cell to growth factors that attempt to bind their receptors at the cell surface. Inhibiting these protein kinases might be a better strategy than using drugs targeted at receptor class because several growth factors can be blocked at the same time. Many pharmaceutical companies are starting early clinical trials to test the efficacy of protein kinase inhibitors in cancer patients.
ZD1839 (Iressa) is a highly specific inhibitor of the EGFR tyrosine kinase inhibitor. It blocks the signal transduction by inhibition of EGFR transphosphorylation and thus targets the same signal transduction pathway as the Mab trastuzumab described above. Preclinical studies have demonstrated that ZD1839 is effective and has good bioavailability. Its toxicity is manageable, with skin rash, nausea, vomiting and diarrhoea being the most common side-effects. In phase I clinical trials, responses were observed in patients with various malignant tumours, in particular non-small-cell lung cancer. Phase II and III studies are ongoing.
STI571 provides the most dramatic example of the potential of this class of agents. A protein called Bcr-Abl is a constitutively activated tyrosine kinase. It is expressed as a result of the juxtaposition of the Bcr and Abl sequences in Philadelphia-chromosome-positive leukaemia (such as chronic myeloid leukaemia [CML]). STI-571 acts as a competitive inhibitor at the ATP binding site of the Abl-kinase. Clinical trials indicate that STI-571 is extremely active in all phases of CML.(8) Fifty-three out of 54 patients in the chronic phase achieved haematological remissions once therapeutic dose levels were achieved. STI571 is also active in CML blast crisis and Philadelphia-chromosome- positive acute lymphoid leukaemia (ALL). Moreover, these responses were achieved without significant toxicity. STI571 has a high degree of specificity, not only for the Abl, but also for the platelet-derived growth-factor receptor (PDGFR) tyrosine kinase and the c-Kit tyrosine kinase. Gastrointestinal stromal tumours (GISTs) have activating mutations of the c-Kit tyrosine kinase. A clinical trial is being held to investigate what effect STI-571 might have on this disease.
Ras proteins – these play a key role in the growth-factor- triggered signalling pathway leading to mitogenesis. Mutations in the Ras oncogenes found in pancreatic, lung, colorectal and thyroid carcinomas, and (in some rare cases) in breast or gynaecological carcinomas, result in a continuously activated Ras protein because of insensitivity to the Ras guanosine triphosphate (GTP)-ase activating protein (GAP), which cycles the Ras protein back to its inactive status. The transforming activity of Ras proteins is dependent on their migration to the plasma membrane. The necessary first step in this process is the addition of a farnesyl group, which is catalysed by the enzyme farnesyl transferase. Inhibitors of farnesyl transferase have shown promising results in preclinical studies, with dramatic tumour reduction in Ras-dependent tumours in mice. Phase I and II clinical trials of several farnesyl transferase inhibitors are ongoing.
2.Inhibitors of angiogenesis
The growth of tumours to a diameter of over approximately 2mm requires the development of new blood vessel capillaries to allow further tumour growth. The endothelial cells of the new capillaries are sufficiently different from those associated with mature vessels to allow selective inhibition. Several endothelial-specific growth factors have been identified. One of these factors – vascular endothelial cell growth factor (VEGF) – can be inhibited by neutralising antibodies, receptor antagonists or anti-VEGF-receptor antibodies. Elimination of this neoangiogenesis can result in tumour dormancy. Such therapy is directed against genetically stable endothelial cells, suggesting fewer problems with drug resistance than conventional chemotherapy.
Some known anticancer drugs (interferon, paclitaxel and vinblastine) seem to be effective, at least in part, as a result of a mechanism based on the inhibition of angiogenesis. An interesting theory is that hormonal ablation might also work by using such a mechanism. Androgens can act as powerful inducers of VEGF. Suppression of VEGF production results in endothelial cell death in immature blood vessels and secondary apoptosis of the tumour cells surrounding the regressing vessels. Oestrogens can have a similar effect on angiogenesis. The therapeutic effect of tamoxifen may be due in part to this phenomenon.
On the other hand, activation of the EGFR as well as the Ras protein seems to be associated with induction or overexpression of VEGF. Inhibition of these receptors was found to suppress VEGF messenger RNA and protein expression in cell culture. Therefore, as for the currently studied receptor inhibitors, the protein kinases mentioned might also have an antiangiogenic effect.
3. Cyclin-dependent kinases (CDKs)
The cell cycle is regulated by CDKs. Cyclin binding to the CDKs is required for kinase activation. CDKs regulate several biochemical pathways that integrate mitogenic and growth-inhibiting signals. They are fully activated by phosphorylation. This is catalysed by the CDK-activating kinase and inhibited by two families of CDK inhibitory proteins (kinase inhibitory proteins and INK4 [inhibitor of cyclin-dependent kinase 4], an inhibitor of CDK4).
Flavopiridol inhibits certain protein kinases, including EGFR, but also inhibits CDK1, 2 and 4. The stauro-sporine derivative UCN-01 is a less specific and less potent synthetic CDK inhibitor, but also acts as a modulator of CDK function through its effect on the CDK checkpoint mechanisms that monitor chromosome integrity. Other synthetic CDK inhibitors are being developed. In the first phase I clinical studies with flavopiridol and UCN-01, some partial responses were observed. Phase II clinical trials are ongoing.
- Fisher B, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90:1371-88.
- Pritchard KI. Is tamoxifen effective in prevention of breast cancer? Lancet 1998;352:800-1.
- Ranson MR, et al. Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol 1997;15:3185-91.
- Senderowicz AM, Sausville EA. Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst 2000;92:376-87.
- Norton L, et al. Overall survival advantage of simultaneous chemotherapy plus the humanized anti-HER2 monoclonal antibody herceptin in HER2-overexpressing (HER2+) metastatic breast cancer. Proc ASCO 1999;18:483.
- McLaughlin P, et al. Rituximab chimeric anti-D20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16:2825-33.
- Vose JM, et al. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin’s lymphoma. J Clin Oncol 2001;19:389-97.
- Mellinghoff IK, Sawyers CL. Kinase inhibitor therapy in cancer. Principles and Practice of Oncology Updates 2000;14:1-11.
European Society for Medical Oncology
European Organisation for Research and Treatment of Cancer (EORTC)
5–9 Nov 2001
Cancer Clinical Trials: Methods & Practice
18–22 Oct 2002 27th ESMO Congress
Novel compounds designed to target directly the abnormal activation of a variety of signalling pathways in the cancer cell will offer a new and more specific weapon against cancer The adverse events of these new drugs will be less severe than those experienced by patients undergoing conventional chemotherapy
Cancer therapy will become more “cancer-type specific”