The Current Status of Cancer Treatment

Until the advent of targeted therapies, dealing with cancer, outside of surgery, was not unlike waging guerrilla warfare on an enemy of unknown size: destroying the whole village was one fear, not knowing how many soldiers lurked in the surrounding hillsides, another. But new monoclonal antibodies and small molecule drugs are designed to concentrate cytotoxicity where needed and reduce damage elsewhere in the body--unlike the one-poison-kills-all-tumors approach that is chemotherapy. Their designs, however, are not perfect, not by a long shot. Among nearly 80 oncology Food and Drug Administration approvals since 1995, the few related to nonspecific chemotherapeutics have been mostly innovations in drug delivery. Gliadel (polifeprosan 20 with carmustine implant), for example, helps carmustine kill brain tumor cells by circumventing its feeble ability to penetrate the blood-brain barrier. Neurosurgeons implant carmustine-impregnated Gliadel wafers into cavities left after tumor removal. The wafers slowly release the drug near remaining tumor cells where, following hydrolysis, its metabolites cross-link DNA by alkylation. Gliadel turns carmustine into a more targeted drug by avoiding the systemic toxicity that would result from carmustine injections. The approvals also show the undiminished importance of coping with symptoms and therapeutic side effects. Relieving pain accounts for a steady stream of drug approvals, along with drugs for such problems as nausea and vomiting, renal toxicity, dry mouth from radiation, and hypercalcemia of malignancy. Contrast agents for diagnostic tumor imaging are also among the new approvals. TARGETING WITH MONOCLONALS Decades in the making, monoclonal antibodies have begun the era of targeted therapy - but only a handful have been approved so far. The first monoclonal antibody-based drug was Rituxan (rituximab), designed for relapsed or refractory CD20-antigen positive B-cell non-Hodgkin lymphomas (NHL). Others include Herceptin (trastuzumab; for breast tumors overexpressing human epidermal growth factor receptor 2), Campath (alemtuzumab; B-cell chronic lymphocytic leukemia), Mylotarg (gemtuzumab ozogamicin; relapsed acute myelocytic leukemia), and Zevalin (90 Y ibritumomab tiuxetan), which binds the same target as Rituxan. Among these, Zevalin is remarkable as a kind of Janus, simultaneously looking at monoclonal technologies past and future. Its amino acids are entirely murine-derived, the last thing one might expect, considering that the long delay between discovering monoclonal antibodies and their arrival in the clinic was mostly due to their murine origin. Their antibodies provoke the human antibody response, fix human complement inefficiently, and have much shorter half-lives than human antibodies. In creating Rituxan, San Diego-based IDEC Pharmaceuticals overcame these problems by grafting mouse variable-region antigen binding sites onto human antibody constant regions. The result was a chimeric monoclonal antibody over 95% human. And the source of Rituxan's grafted binding sites? Zevalin. Zevalin, say Pratik Multani and Peter Pieslor, IDEC medical affairs officers, complements Rituxan by killing NHL cells through a different mechanism. Binding of Rituxan to CD20 on the tumor cell surface recruits the immune system to destroy the cell. Zevalin kills with the radionuclide yttrium-90 that is tightly bound to the antibody by means of a covalently linked chelator. Yttrium-90 releases a beta particle that can penetrate surrounding tumor cells over a 5-mm radius, leaving cellular free radicals, then cell death, in its wake. As a radio-labeled antibody, murine origin is an advantage for Zevalin. A shorter half-life decreases yttrium-90 circulation time. And Zevalin's incidence of provoking human antibodies is low, possibly due to its dose being orders of magnitude smaller than that of Rituxan. The vastly lower required dose reflects the potency of adding the radionuclide. Zevalin is used in tandem with Rituxan. A NHL patient receives Rituxan, then Zevalin several hours later. Rituxan, say Multani and Pieslor, lets Zevalin achieve greater tumor penetration. Clinical trials, they say, demonstrate that Zevalin plus Rituxan significantly increase overall rate of response and extend median response duration beyond what Rituxan offers alone. Approved in 2002, Zevalin is the first radioimmunotherapeutic, adding a new dimension to radiotherapy.2 Mylotarg, approved in 2000, similarly opened doors for chemotherapy. Mylotarg is a chimeric antibody covalently linked to calicheamicin, an antibiotic. When Mylotarg binds CD33 on acute myeloid leukemia cells (CD33 antigen is present for about 80% of AML patients) the antibody-CD33 complex is internalized. Inside the cell, lysosomes release calicheamicin from the antibodies, so that it can bind DNA, cause double-stranded breaks, and apoptosis. Zevalin and Mylotarg show that cytotoxic mechanisms for monoclonal antibodies would do more than activate the immune response. Gleevec (Imatinib) blocks reception of a growth signal… Click to view an enlarged diagram (29K) TARGETING WITH SMALL MOLECULES Small organic molecules can also target those critical to cancer growth and survival. If anyone had doubts, Gleevec (imatinib) for chronic myelogenous leukemia (CML) challenged them. Following remarkable clinical trials--in Phase I, 31 positive responses in 31 CML patients who had failed standard therapy--FDA approved Gleevec in record time in 2001. A single event triggers CML: A chromosomal translocation fuses genes Bcr and c-Abl, encoding the fusion protein Bcr-Abl, which has unregulated tyrosine kinase activity. Precisely how this activity leads to leukemia is still under investigation, but before blast crisis, when mutations in additional genes drive CML, Gleevec inhibition of BCR-Abl activity controls the disease. Its mild side effects let most early-stage CML patients live in relative comfort for years. From such success comes a new notion, says Gleevec pioneer Brian J. Druker, of Oregon Health & Science University Cancer Institute, in Portland: "It's becoming more popular in cancer circles to talk about cancer as a chronic disease, one that we can control." But he hopes for more: "The goal still has to be moving from control to cure." Possible ways to eradicate the last remaining abnormal cells in patients include combining Gleevec with previous CML treatments such as interferon, or with immune therapy, he says. Other targeted therapies have emerged from Gleevec's inhibition of the structurally similar tyrosine kinases c-kit and PDGFR (platelet-derived growth factor receptor). Gleevec is approved for gastrointestinal stromal tumors (GIST), which have overactive c-kit, and can control hypereosinophilic syndrome, a rare leukemia implicating abnormal PDGFR activity.1 In the future, says Druker, whenever research reveals cancers with dysfunctional Gleevec targets, adding Gleevec to the current therapy protocols will be considered. Another small molecule for targeted therapy, AstraZeneca's Iressa (gefitinib), approved in May, is the first of a new drug class, epidermal growth factor receptor (EGFR) inhibitors.3 It sprang "from the hypothesis that EGFR was overexpressed in a number of common solid tumors, particularly lung, breast, and colon," says Les Hughes, vice president, global, cancer, and infection research at AstraZeneca. "At high levels of expression, tumors were more aggressive; there was a much greater chance they would be invasive. It was also known that blocking the receptor decreased proliferation of tumors." Instead of blocking EGF binding to its receptor, Iressa "blocks signaling of the receptor," Hughes says. EGFR is a receptor tyrosine kinase. Iressa works by blocking phosphorylation of the receptor, which is necessary for signaling downstream, he adds. The FDA approved Iressa as a third-line monotherapy for advanced non-small cell lung cancer (NSCLC)--if first- and second-line therapies failed. In the United States, 80% of lung cancers are of this type. In the clinical trial that led to the approval, about 10% of patients (more than half with tumors resisting two prior treatments), responded with at least 50% tumor shrinkage for at least one month; median response duration was seven months; side effects were mainly nausea and vomiting, diarrhea, and rash. SUSCEPTIBILITY AND RESISTANCE Medical oncology's eternal question is how best to use the drugs it already has. Conclusions are only temporary, however, until better drugs come along-- witness Gleevec pushing interferon out of first-line CML therapy. Finding out where Iressa fits in, including whether it deserves a place in first- or second-line NSCLC therapy, will be complicated, says Hughes, because the cancer treatment market is "fragmented." In colon cancer, for example, "you have the spectrum from post-surgery, when the main tumor has hopefully been removed, through first recurrence, through subsequent treatment failures, through to last resorts. Certain agents are used in those particular sectors. AstraZeneca will have to do the clinical trials to show in which sectors Iressa would be most effective." Answering best-practice questions involves drugs new, old, and even sometimes reclaimed, as with notorious thalidomide, the 1950s sedative belatedly discovered to cause birth defects. Today, as Thalomide, it is approved for the treatment of leprosy. But its immunomodulatory and antiangiogenic properties make it a candidate for treating multiple myeloma. A recent clinical trial4 reports favorably on thalidomide treatment of multiple myeloma. Perhaps someday Thalidomide may be tested in combination with Velcade (bortezomib), a proteasome inhibitor approved in May for multiple myeloma therapy (see The Ubiquitin System in Cancer). MYSTERIES Behind clinical trials is the enduring question of why antitumor agents work for some types of cancers but not others. Susan Band Horwitz, professor and co-chair of molecular pharmacology at the Einstein College of Medicine in the Bronx, NY, has pondered this many times. Take Taxol (paclitaxel), which she has shown causes cell death by stabilizing cytoskeletal microtubules, inhibiting cell division. Taxol should work against many more cancers than it does. Notably, she says, no one knows why it is not effective for leukemias and colon cancer. And that's but one example. "Why aren't methotrexate and 5-fluorouracil more widely useful? Why can't the vinca alkaloids treat breast cancer?" The mystery applies equally to targeted drugs treating one kind of tumor. While EGFR levels seem to correlate with the severity of NSCLC, "when you look at [Iressa] responders versus nonresponders in the clinical trials," says Hughes, "response is not related to the level of EGFR on the surface of the tumors." The other great puzzle is drug resistance. "People can go into remission and then a few years later relapse with tumors that no longer respond to the old drugs," says Horwitz. The reason usually is that the drug has selected for variant tumor cells that grow in the drug's presence. Tumors have many resistance mechanisms; certainly, Horwitz says, and this is true for resistance to Taxol. But since drug resistance is studied mostly in vitro, "we don't know in human tumors what is the relative importance of different forms of drug resistance." Consider P-glycoprotein, the efflux pump that ejects Taxol (and many other hydrophobic chemo-therapeutics) from the cell. "We don't know how many Taxol-resistant phenotypes in tumors are due to P-glycoprotein," she adds. This, however, she does know: "If there weren't such a thing as drug resistance, we would do pretty well at killing tumors." Tom Hollon (thollon@starpower.net) is a freelance science writer in Rockville, Md. References 1. J. Cools et al., "A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome," New Engl J Med, 348:1201-14, 2003. 2. M.E. Juweid, "Radioimmunotherapy of B-cell non-Hodgkin's lymphoma: from clinical trials to clinical practice," J Nucl Med, 43:1507-29, 2002. 3. C.A. Ritter, C.L. Arteaga, "The epidermal growth factor receptor-tyrosine kinase: a promising therapeutic target in solid tumors," Seminars in Oncology, 30(Suppl 1):3-11, 2003. 4. A. Anagnostopoulos et al., "Thalidomide and dexamethasone for resistant multiple myeloma," Brit J Haematol, 121:768-77, 2003. FALSE CURES Cancer cure-alls have run the gamut from apricot pit extracts to coffee enemas, to crystals, mistletoe, shark cartilage, oxygen, and music. And why do bogus cancer cures spring eternal? Money, in part. "Anything that's quack will last as long as it is marketable," says Stephen Barrett of the National Council Against Health Fraud. A retired psychiatrist, Barrett monitors scams online at www.quackwatch.org. It's also who the grifters are. "Many are paranoid individuals who have messianic feelings that they're going to save the world--and coincidentally make a lot of money," Barrett says. Plus, imprisonment is rare. "Most people who do this know that if they're caught they're going to come out ahead anyway." So it's news when the government finally moves against a long-term scam, as happened in May when the US Federal Trade Commission asked a court to curb the marketing of Coral Calcium Supreme, a calcium supplement derived from marine coral. Scientific evidence did not support cancer-cure claims broadcast via television infomercials, the FTC argued. Other calcium-coral marketers have received FTC warning letters demanding that false advertising of undocumented health benefits cease.

The Current Status of Cancer Treatment

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