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Proceedings of the First International Conference |
University of Colorado Cancer Center, Denver, Colorado
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ABSTRACT |
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INTRODUCTION |
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B (NF-B), cellular inhibitor of apoptosis protein, and X-linked inhibitor of apoptosis protein, are regulated by the proteasome.
In Vitro Studies of Bortezomib.
The mechanism of cytotoxicity of bortezomib has been examined in studies of cell lines of different histology (1)
. Ling et al. (2)
examined the effects of bortezomib in human non-small cell lung cancer cell lines, including those with p53 wild type, p53 mutant, and p53 null phenotypes. A concentration- and time-dependent cell cycle blockade in the G2-M phase was observed, without affecting microtubule polymerization or depolymerization. Bortezomib produced an increase in cyclin B and cyclin A with activation of cyclin B and cyclin A kinases. Increases in the cdk inhibitor p21cip/waf-1 were also observed, as was activation of caspase-3.
Sunwoo et al. (3)
examined the effects of bortezomib on human squamous carcinoma cell lines. Bortezomib produced cell growth inhibition that was associated with inhibition of NF-B activation and increased caspase-induced apoptosis. In vivo, doses of 1–2 mg/kg three times weekly inhibited the growth of human squamous carcinoma xenografts in athymic mice. Adams et al. (4)
showed that bortezomib inhibited the growth of human prostate adenocarcinoma cell lines in vitro and in vivo in athymic nude mice (4)
. Exposure of lung cancer cells to bortezomib produced an increase in p21, cell cycle accumulation in G2-M, activation of caspase, and increased apoptosis (5)
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Hideshima et al. (6)
showed that bortezomib inhibited the growth of human multiple myeloma cell lines by inhibiting proliferation and inducing apoptosis. Bortezomib induced IB degradation and inhibited p44/42 mitogen-activated protein kinase activation. Additive growth inhibition was observed with dexamethasone. Using DNA array analysis, Mitsiades et al. (7)
showed that bortezomib led to down-regulation of genes involved in growth/survival pathways, up-regulation of genes involved in proapoptotic cascades, and up-regulation of heat-shock protein genes in multiple myeloma cells.
Human Clinical Studies.
Orlowski et al. (8)
conducted a Phase I trial of bortezomib in 27 patients with refractory hematological malignancies. Patients received bortezomib i.v. twice weekly for 4 weeks at 0.40, 1.01, 1.20 or 1.38 mg/m2 followed by a 2-week rest. Dose-limiting toxicities that were observed at doses above 1.04 mg/m2 (the maximum tolerated dose) included thrombocytopenia, fatigue/malaise, hypokalemia, and hypona-tremia. Pharmacodynamic studies showed that bortezomib induced 26S proteasome inhibition in a time- and dose-dependent manner. Responses were observed in patients with multiple myeloma, mantle cell lymphoma, and follicular lymphoma.
Richardson et al. (9)
reported the results of a large 202 patient Phase II study of bortezomib in patients with relapsed/refractory multiple myeloma termed the Stanford University Medical Media and Information Technologies trial. All patients had received at least two prior therapies with a median of six. Response rates were assessed by the criteria of both Blade et al. and the Southwest Oncology Group (10
, 11)
. The Blade criteria required 
50% reduction in serum myeloma protein and 90% reduction of urine myeloma protein on at least two occasions for a minimum of 6 weeks, as well as stable bone disease and normal calcium. The Southwest Oncology Group criteria required 75% reduction in serum myeloma protein and 90% reduction of urine myeloma protein on at least two occasions for a minimum of 6 weeks, along with stable bone disease and normal calcium. Bortezomib was administered at 1.3 mg/m2 i.v. push twice weekly on days 1, 4, 8, and 11 in a 3-week cycle for a maximum of 8 cycles. The objective response rate was 27.7% ± 7% using the Blade criteria and 17.6% ± 6% using the Southwest Oncology Group criteria. Responses were independent of the number or type of prior therapy. The median duration of response was 365 days. Toxicity included 14% of patients having at least one grade 4 toxicity. These grade 4 toxicities included thrombocytopenia (3–4%) and neutropenia (3–4%). Therapy was discontinued because of peripheral neuropathy in 6%, gastrointestinal effects in 5%, thrombocytopenia in 4%, and fatigue in 2%.
Bortezomib was also studied in a small, multicenter dose-ranging study in refractory multiple myeloma patients termed the CREST trial (12) . Bortezomib was administered as 1.0 mg/m2 or 1.3 mg/m2 i.v. push on the same schedule. There were 53 evaluable patients who had received a median of 3 prior therapies. Major responses were seen in 30% of patients at the 1.0 mg/m2 dose and 38% of patients at the 1.3 mg/m2 dose. The FDA approved bortezomib for use in the treatment of relapsed and refractory multiple myeloma patients based on these data. However, there are no controlled trials demonstrating a clinical benefit such as improvement in survival. Such trials are planned or in progress.
Bortezomib in Lung Cancer.
There are no published trials using bortezomib in lung cancer patients, although a number of such trials are ongoing. These trials include a randomized Phase II study evaluating bortezomib alone and bortezomib plus docetaxel in the second-line therapy of advanced non-small cell lung cancer. There is also a Southwest Oncology Group Phase II trial of single-agent bortezomib (1.5 mg/m2 i.v. days 1, 4, 8, 11 every 3 weeks) in the second-line setting in advanced SCLC for both platinum-sensitive and platinum-refractory patients.
There are a number of ongoing combination Phase I trials including bortezomib combined with the following: gemcitabine; etoposide plus cisplatin; paclitaxel plus carboplatin; and gemcitabine plus carboplatin. The results of these studies should lead to Phase II studies in advanced non-small cell lung cancer, assuming bortezomib shows activity in the ongoing single-agent trials.
Bortezomib in Other Cancers.
Preclinical studies of breast, pancreatic, lung, and ovarian cancers showed that bortezomib inhibited tumor growth (13, 14, 15)
. Bortezomib demonstrated antiangiogenic effects in many of these studies. In these models, bortezomib exhibited the greatest activity when combined with standard chemotherapeutic agents. Phase I trials showed that serum concentrations can be achieved that produce antitumor effects in preclinical models (13
, 15)
. The results of a Phase II trial of bortezomib in renal cell cancer was recently reported (16)
. There was one objective response among 21 evaluable patients.
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OPEN DISCUSSION |
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Dr. Paul Bunn: Assuming you inhibit it for 72 hours, so then 3 days later it is reasonable to give it again. But do you want to have it down forever or do you want to have it down intermittently?
Dr. Adjei: What happened was what you alluded to: PS-351 does not hit a specific target since the proteasome degrades a lot of proteins. In fact, before our Phase I study, everybody predicted that this agent was going to be very toxic, so it couldn’t be given continuously. In our Phase I trials, we did it twice a week for 4 weeks, then 2 weeks off, but a lot of patients couldn’t do the full 4 weeks; by the third week they were very tired. So we looked at an amended schedule of twice a week, 2 weeks on and 1 week off.
Dr. Bunn: many proteins we inhibit intermittently, so how do you know that was the best strategy to give it as long as you could and then rest because of toxicity?
Dr. Adjei: We had nearly 40 patients altogether, and we didn’t see any hint of activity. That was with both schedules. Based on all the data, we felt that this might be a good drug to combine with chemotherapy, in terms of reversing resistance, because of the NF-B effect. When you give any DNA damaging agent, inhibitory kappa B (IB) is degraded and NF-B activated, which activates all these antiapoptotic proteins because it’s a survival factor. Since its degradation is through the proteasome, if you can inhibit the proteasome, then you inhibit activation of NF-B and so make the cells sensitive to chemotherapy. So it may be that for solid tumors, PS-341 might be a great drug to combine with chemotherapy.
Dr. Thomas Lynch: You would argue that the combination should be with DNA damaging agents as opposed to antimicrotubule agents?
Dr. Adjei: We did a Phase II monotherapy study in melanoma that was negative, and we are completing a Phase I study in combination with paclitaxel/carboplatin. We have had four out of six melanoma patients respond. It is anecdotal, but it is interesting that on its own, PS-341 did nothing, but with paclitaxel/carboplatin there were responders. In terms of sequencing therapy, we have to be careful because sometimes it depends on the cell line you use. So there are conflicting data, with some suggesting the PS-341 first, followed by the taxane, is synergistic. In our studies, the regimen that is going forward is the PS-341 day 1 and paclitaxel/carboplatin day 2. The reverse we stopped because it was toxic with not as much activity.
Dr. David Gandara: We have not only in vitro but also xenograft data showing that PS-341 can be antagonistic depending on how you combine this drug with chemotherapy. So I think that’s the difficulty. It has biologic activity, since it is very active in myeloma as a single agent and has a little bit of activity in solid tumors, because there are single agent responses in lung cancer, breast cancer, lymphomas, etc. Based on the data, the issue is not only sequence; you have to separate the drugs. We actually have revised out protocols so that there is about a 48-hour separation between the drugs. Now I don’t know whether that is just a xenograft phenomena or not, but perhaps just taking the schedule that they used as a single agent and throwing chemotherapy together with it isn’t really giving PS-341 its best shot.
Dr. Geoffrey Shapiro: If you believe that the potentiation is via the NF-B pathway and that all you have to do is reduce NF-B, then the sequencing with chemotherapy probably shouldn’t matter. However, this drug has very complex effects at the G2-M boundary. Cyclin A and B activity go up, but p27 is potently induced. That is predicted to induce a G2 arrest, and so one can imagine if you stop at the G2 boundary, it will be antagonistic with the taxane, as you will prevent the entry into mitosis required for the taxane to work. Probably taxane has to be first. And, not only do you have to get the sequence right, but you have to get the interval between the two drugs right. So, the combination with taxane in particular is very complex and that may be part of the problem.
Dr. Adjei: Sometimes you get surprised in the clinic. We had a group of patients who got taxane first, the other group got PS-341 first, day 1 or day 2. Taxane first was not as good as PS-341 first, based just on toxicity. That was Phase I, so if you have one response in that group and three in this other group, what does it mean? It doesn’t mean a whole lot; we have to go with toxicity data, in terms of selecting the combinations we could give.
Dr. Lynch: So, there have been some, at least, two reports of responses as a single agent. There is at least some hint that while PS-341 is a weak agent in non-small cell lung cancer, there might be some activity in lung cancer. I think the comments on how one can combine this with chemotherapy are really terrific.
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FOOTNOTES |
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Requests for reprints: Paul A. Bunn, Jr., University of Colorado Cancer Center, 4200 E. 9th Ave. B 188, Denver, CO 80262. Phone: (303) 315-3007; Fax: (303) 315-3304; E-mail: paul.bunn{at}uchsc.edu
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