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Feature Articles : May 1, 2007 ( )
Navigating Complex Pathways in Cancer
Low Molecular Weight Compounds Hold Promise as Inhibitors of Tumor Growth!--h2>
Despite decades of research, cancer remains the leading cause of death by disease in the western world. However, advances in R&D as well as increased understanding of the complex pathways, molecular mechanisms, and pathophysiology of human cancer have opened up new opportunities for drug development. At the “4th Cancer Drug Research and Development” conference held recently in Philadelphia, an array of topics in the R&D space were covered.
Inhibitors of VEGF Signaling
Researchers at AstraZeneca (www.astrazeneca.com) discussed some of the challenges in the clinical development of small molecule inhibitors of VEGF signaling. “We spoke specifically of two compounds we have in the clinic, ZD-6474 (Zactima) and AZD-2171 (Recentin™),” said Charles Morris, vp, clinical development projects, oncology. “As early as Phase I, we saw clinical response in non-small cell lung cancer for ZD6474. We went into this open-minded, but this early clinical signal guided the further development direction of this compound, which is also being investigated in other tumor types.”
Phase II trials were randomized studies for both monotherapy and combination therapy. The design and evidence yielded enough to send ZD6474 to Phase III studies looking at monotherapy, and in combination with cytotoxic chemotherapy. “We had interesting results,” Morris said. “Historically, EGFR-TKIs had demonstrated activity in monotherapy, but not combination therapy. However, with the lung cancer patients, there seemed to be signs that the combination therapy was also working, suggesting that the targeting of two pathways—EGFR and VEGFR—was producing a differentiated profile for the drug. In addition, the RET-kinase inhibitory activity of the drug has led to initial investigation in medullary thyroid carcinoma where preliminary data has shown calcitonin reductions and radiographic responses. Phase II work is also ongoing in other tumor types including breast, glioma, and prostate cancers.”
The preclinical data for Recentin showed relatively selective inhibition of VEGF receptors 1, 2, and 3. “Demonstration of biological activity is a challenge, but extensive use of biomarkers early in the development process has allowed us to define a biologically active dose range despite the relatively low numbers of radiographic responses seen with this class of agents. The biomarker data gave us the confidence to make go/no go decisions, and this agent is now under investigation in a broad range of settings,” Morris said.
“We still don’t know whether it’s more important to have a specifically targeted compound than something that hits multiple targets,” Morris added. “When you have something that hits multiple targets, you may be more likely to see efficacy through inhibition of multiple pathways, but there may equally be an increased likelihood of off-target toxicity.”
The Preclinical Setting
Merck & Co.’s (www.merck.com) Nancy Kohl, senior director of cancer research, presented a talk on the preclinical characterization of a small molecule inhibitor of c-Met kinase activity. “I presented an update of a compound we are working with that targets c-Met,” said Kohl. “It is a molecule that belongs to a chemical class identified through high-throughput screening and also a potent inhibitor of c-Met and RON that inhibits just a few additional kinases involved in angiogenesis.”
The compound also inhibits physiologically relevant mutants of Met, and inhibits signaling pathways downstream of the receptor. “It is active in cells, inhibiting the processes of mitogenesis, motogenesis, and morphogenesis,” Kohl said. “We were able to show the activity using cell-based assays that measure each of these particular functions.”
Kohl said that her team used the human tumor cell line, GTL-16, in which the Met gene is amplified and the pathway is activated, to evaluate the in vivo antitumor activity of the compound. They found that not only was the 100 mg/kg dose administered twice daily well-tolerated, but also that there was tumor stasis, inhibition of the downstream pathways, and an increase in apoptosis.
“One of the biggest challenges we find is understanding which cancer patients will benefit from treatment with a particular therapy. Cancer is a heterogeneous disease, and effective treatment requires matching the therapy to the tumor genetics,” said Kohl. “To meet the challenge, we surveyed dozens of tumor cell lines for sensitivity to to the compound. Those lines with an activated c-Met pathway were exquisitely sensitive.”
Methionine Aminopeptidase Type 2
Praecis Pharmaceuticals, now GSK-Boston (www.gsk.com), is working with methionine aminopeptidase type 2 (MetAP-2), a bifunctional protein vital in the regulation of protein synthesis and post-translational processing. It is also the molecular target for PPI-2458, which is in the clinic now for patients with non-Hodgkins lymphoma (NHL) and solid tumors.
“The first-in-its-class inhibitor, TNP-470, failed in the clinic because of significant CNS toxicities,” explained William Westlin, senior vp of preclinical research. “The main challenge was to find an orally available inhibitor of MetAP-2 that avoided these toxicities while maintaining potent antiangiogenic and antiproliferative activity.”
PPI-2458 is structurally related to TNP-470 and is an orally available, irreversible inhibitor of MetAP-2, which inhibits angiogenesis and proliferation of sensitive cancer cell types. “One of the key findings that helped guide the early clinical development was that PPI-2458 has a direct effect to inhibit cancers derived from germinal center B cells including diffuse large B cell lymphoma and follicular lymphoma, the predominant NHL cancer types,” Westlin said.
The rationale for using PPI-2458 in non-Hodgkin’s lymphoma was that the treatment of animals with PPI-2458 resulted in a reversible depletion of germinal center B cells in lymph node and spleen. “PPI-2458 is also active in vivo in preclinical models of NHL tumor growth as monotherapy or in combination with standard of care, CHOP, or Rituxan,” Westlin said. “Since MetAP-2 may play a role in the growth and survival of malignant B-cells lymphomas, PPI-2458 may turn out to be a significant therapeutic intervention in the treatment of specific B-cell malignancies.”
New Indications for Old Compounds
Atiprimod is a small molecule inhibitor of PI-3K/Akt and STAT-3 pathways that Callisto Pharmaceuticals (www.callistopharma.com) is currently testing in the clinic. In the azaspirane class of compounds it was initially developed as a potential treatment for rheumatoid arthritis. Atiprimod successfully completed single and multiple dose Phase I trials, “but Phase II trials were never implemented, and it sat on the shelf for a while,” said Kunwar Shailubhai, senior vp of discovery research for Callisto.
In addition to showing safety and efficacy, Atiprimod also demonstrated that it lowered serum IL-6 levels in a dose-dependent fashion and lowered other cytokines as well. “Specifically, we looked at IL-6 and VEGF, which are generally recognized as playing a major role in the pathophysiology of multiple myeloma,” said Shailubhai. “We also noted that it lowered TNF-a and IL-1 levels, which are important growth factors associated with carcinogenesis. Based on this information, we decided that this compound could have therapeutic properties for patients with multiple myeloma and other solid cancers.”
Given what Shailubhai and his team know about the antiproliferative and anti-angiogenic properties of atiprimod and the bioavailability of the compound, they focused their studies on patients with advanced carcinoid cancer in which a majority of patients have liver metastases. They also noticed that metastatic cells from different tumor types were highly sensitive to the antiproliferative activity of atiprimod.
Clinical results from Phase I trials in advanced carcinoid patients showed a clear-cut reduction in disease symptoms, according to Shailubhai.
Recently, Shailubhai also demonstrated the therapeutic potential of atiprimod in hepatocellular carcinoma. This study, recently published in Molecular Cancer Therapeutic, opens other therapeutic applications of atiprimod.“Another characteristic we’ve seen is that it inhibits activated-osteoclast-driven bone resorption, which is a key factor associated with the pathology of multiple myeloma, which could be important in treating other osteolytic bone diseases,” added Shailubhai.
Tracking Antitumor Activity
Sridhar Rabindran, associate director of oncology at Wyeth (www.wyeth.com), discussed the clinical antitumor activity of HKI-272, which is an irreversible binding inhibitor of the ErbB family of receptor tyrosine kinases, currently in Phase II clinical trials. “There are three ErbB inhibitors out in the clinic right now, including one that was recently approved. HKI-272 is different from these compounds in two ways—a pan-ErbB inhibitor it inhibits all members of the ErbB family and is also an irreversible-binding inhibitor,” said Rabindran.
“The molecule forms a covalent bond with a cysteine residue within the ATP-binding site,” Rabindran said. “This results in prolonged inhibition of the target, which we confirmed in cancer cells and in animal models.”
Not only did they show good activity in a variety of cancer cell lines, but the molecule worked as Rabindran and his team expected. “Ultimately, it resulted in cell-cycle arrest,” said Rabindran.
In xenograft models, excellent antitumor activity at a once-daily oral dose of 10-40 mg/kg was observed, according to Rabindran.
One problem is that mutations cause tumors to become resistant to treatment. About half of the patients with lung cancer who are treated with the existing ErbB inhibitors tend to develop a secondary mutation, wherein the receptor is resistant to treatment. “HKI-272 appears to retain activity against these mutations in preclinical models,” Rabindran said. “In vitro data shows that the mutant receptors are not resistant to our irreversible binding inhibitor. Why, is a mystery we are trying to solve.
“In Phase I, HKI-272 showed good antitumor activity in patients with breast and lung cancers who were heavily pretreated,” said Rabindran. “We are encouraged by these results and hope that the irreversible aspect of this compound will allow us to effectively treat patients who have progressed on other ErbB therapies.”
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