Shahin Rafii believes in doing more with more.
Angiogenesis was the topic of an ASH/ASCO joint session held at the ASH annual meeting in Orlando, Fla., on Sunday, and Rafii, who is at Weill Cornell Medical College in New York, spoke about different kinds of combination therapy that angiogenesis can be a part of.
"Even though leukemias are liquid tumors, they take advantage of the mechanisms of angiogenesis," Rafii told the audience. They do that by inducing endothelial cells to produce growth factors, and so the eradication of tumor vessels "requires combination therapy to target both endothelial and perivascular cells," he said.
Rafii also showed data suggesting that while neither VEGFR1 nor VEGFR2 receptor blockade by itself was sufficient to fully put an end to tumor growth, combination therapy targeting both receptors did the trick.
"You're not going to block tumor growth until you block all VEGF receptors and understand how these guys talk to each other," Rafii said. "This axis of evil cannot be overcome" through monotherapy.
Another speaker in the ASH/ASCO joint session, Brian Rini, of the Cleveland Clinic, began by pointing out that in his specialty of kidney cancer, anti-angiogenesis drugs have made an enormous difference. Kidney cancer is, in fact, the only solid cancer where anti-angiogenesis drugs by themselves have been useful.
Pfizer Inc.'s Sutent (sunitinib) and Onyx Pharmaceutical's Nevaxar (sorafenib) are approved specifically for renal-cell carcinoma; Genentech Inc.'s Avastin is not approved for kidney cancer but is used off-label to treat the disease, and because it was the first anti-angiogenesis drug available, clinicians have accumulated plenty of experience with using it for kidney cancer.
Despite the fact that all three drugs target angiogenesis as part of their mechanism of action, Rini said that in kidney cancer patients, the Sutent response rates are similar in patients who have been treated with Avastin and those who haven't. "Clearly these approaches are not identical," he said, "and patients can enjoy the benefits of sequential therapy."
Rini also pointed out that a cure is not the only goal worth pursuing. "For a group of patients, progression-free survival may be the best that we can do at this time," he said, and pointed out that in some cases, the progression-free survival news may be better than formal criteria have been able to show.
He showed slides displaying tumors that, despite not shrinking if they were measured by classical measures such as diameter, showed obvious changes for the better. Also, reduced blood flow within the tumor leading to areas of cell death in tumor tissue is another improvement not captured by typical measurements, and so is cavitation, which leaves a tumor with the same diameter, but basically hollow.
He added that "for a clinical researcher, that's not so bad," because in the end, if a drug works, patients are unlikely to complain that they don't know why.
In the October 2006 issue of Journal of Clinical Investigation, researchers from the University of California at San Francisco; New York University; Carlsbad, Calif.-based Cell-Matrix Inc. and Pfizer Inc., of New York, reported preclinical data showing that after withdrawal of anti-VEGF therapy, tumors rapidly regrew blood vessels and that they used a basement membrane scaffold of sorts that is not destroyed by the anti-angiogenic therapy. The researchers concluded that targeting the basement membrane blood vessel "sleeves" as well as the vessels themselves could be a useful combination approach.
Greg Plowman is senior director of tumor biology and angiogenesis at Genentech, although Genentech, of South San Francisco, was not involved in the research reported in JCI.
Plowman's take on the paper added another angle to Rini's contention that current measurement criteria are anything but perfect. Anti-angiogenic drugs usually are given as combination therapy with chemotherapy, he said, and "usually when someone starts to progress, they discontinue the treatment. The paper suggests that may not be such a good idea," he told BioWorld Today, because "resistance to chemo does not mean resistance to that vascular mechanism."
A recent paper in Cell claimed, based on mathematical modeling, that harsh conditions such as the hypoxia presumably induced by blocking angiogenesis actually might increase the chances of a tumor metastasizing. Plowman was highly skeptical of that paper's conclusions, noting that the authors did not take angiogenesis into account directly in the models (though they did address hypoxia, which presumably would be causally related to the blood supply level in a tumor). Plowman said that the clinical data, if anything, supported the idea that preventing angiogenesis will prevent metastasis, and that results in the clinic are what counts in the end. "I'd go with the clinical data before I'd go with the theory."
But he did note that the work might suggest the opportunity for yet another combination therapy. Harsh conditions within the tumor might be exactly the types of environment that cancer stem cells thrive in. If confirmed experimentally, manipulating the tumor environment accordingly might be a new road to take in the fight against cancer, Plowman said, and "no therapy today is even addressing that."
In other news reported at the meeting:
Final Phase III data from university researchers show that Genzyme Corp.'s MabCampath (alemtuzumab) is superior to chlorambucil for patients with previously untreated B-cell chronic lymphocytic leukemia. Also, final Phase II results showed that Celgene Corp.'s Revlimid (lenalidomide) can provide durable results for patients with myelodysplastic syndromes, helping them to achieve blood transfusion independence and remain transfusion-free with long-term follow-up approaching four years.
Millennium Pharmaceuticals Inc. said several clinical trials showed that Velcade (bortezomib) in combination with a variety of agents, including Doxil and dexamethasone, produced consistently high complete and near-complete response rates in newly diagnosed multiple myeloma patients. Other studies demonstrated overall response rates as high as 75 percent for combination therapies across four subtypes of non-Hodgkin's lymphoma (NHL): follicular, marginal zone, mantle cell lymphoma and T-cell lymphoma.
Also, MGI Pharma Inc. said Dacogen (decitabine) was the subject of 16 presentations, with Phase II findings demonstrating its activity in elderly patients with acute myeloid leukemia; partners AEterna Zentaris Inc. and Keryx Biopharmaceuticals Inc. said interim Phase II results showed perifosine alone or in combination with dexamethasone has activity in patients with advanced, relapsed and refractory multiple myeloma; and Cell Therapeutics Inc. reported Phase II results showing that CPOP combination therapy with pixantrone produced a 73 percent overall response rate, including 47 percent experiencing complete disappearance of their tumors, in patients with relapsed aggressive NHL.
Gloucester Pharmaceuticals Inc. said Phase II trials of romidepsin demonstrated its benefits in refractory cutaneous T-cell lymphoma and peripheral T-cell lymphoma, with overall response rates of 32 percent and 30 percent in the two indications, respectively. Bioenvision Inc.'s Phase II studies in adults with acute myeloid leukemia with Evoltra (clofarabine) showed significantly higher response rates and improved survival compared to the current standard of care, especially in high-risk subgroups.
Phase II findings from ViroPharma Inc. demonstrated maribavir's anti-cytomegalovirus activity in stem cell transplant patients. Pharmion Corp. said three studies of Vidaza (azacitidine) demonstrated its clinical activity in combination with HDAC inhibitors for higher-risk myelodysplastic syndromes and acute myelogenous leukemia. CuraGen Corp. and TopoTarget A/S said preliminary Phase II results demonstrated that PXD101 was well-tolerated following intravenous administration in patients with advanced multiple myeloma, with patients achieving clinical benefit from PXD101 in combination with dexamethasone.
Biogen Idec Inc. said Phase I/II data suggested that lumiliximab may be synergistic with fludarabine, cyclophosphamide and rituximab (FCR), an emerging standard of care for chronic lymphocytic leukemia patients. Medarex Inc. detailed safety and response data in patients treated with ipilimumab (MDX-010) for lymphomas and leukemia from two separate Phase I and Phase I/II trials.
Innovive Pharmaceuticals Inc. said preliminary Phase I data showed INNO-406's clinical activity in chronic myelogenous leukemia patients resistant to Gleevec and Tasigna, and EntreMed Inc. released the results of in vitro and in vivo preclinical studies showing a treatment benefit in multiple myeloma with the combination of Panzem (2- methoxyestradiol, or 2ME2) and Velcade over either agent used alone. ZymoGenetics Inc. reported Phase Ib results showing that treatment with atacicept was well tolerated and drug activity was demonstrated by consistent biologic marker responses in NHL and multiple myeloma patients.
ImmunoGen Inc. said initial Phase I findings showed evidence of anticancer activity in multiple myeloma patients receiving the higher of the two huN901-DM1 dose levels evaluated to date; XOMA Ltd. and Novartis AG reported preliminary Phase I results on HCD122 in patients with relapsed and refractory multiple myeloma and chronic lymphocytic leukemia; and Seattle Genetics Inc.'s SGN-40 demonstrated activity in patients with both relapsed/refractory NHL and multiple myeloma.