Page 985 - Hematology_ Basic Principles and Practice ( PDFDrive )

868 Part VII Hematologic Malignancies

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in cell cycle progression (P21 , P27 Kip1 ), oncogenesis (P53, IκB), Pharmacology of Bortezomib
apoptosis (BCL2, BIRC2, BIRC3, BIRC4, Bax), and, more recently, Bortezomib is primarily metabolized through cytochrome P450 (CYP)
DNA repair (DNA-PKcs, ATM). Loss of IκB destabilizes NFκB, and not via phase II pathways (e.g., glucuronidation and sulfation). In
reducing expression of a critical plasma cell cytokine stimulatory vitro studies indicated that the primary metabolic pathway was debo-
molecule, interleukin (IL)-6 (see Chapter 86). The process of cell death ronation mediated by CYP3A4. Bortezomib was also metabolized by
appears to be p53 independent and to result in mitotic catastrophe, CYP2D6, but the rate of metabolism was slower than that observed
although the classical caspase 8-dependent apoptosis pathway has also with CYP3A4. The deboronated metabolites have been shown to
been implicated. A recent study found a strong correlation between be inactive in the 20S proteasome assay. Bortezomib rapidly exits
immunoglobulin production and apoptotic sensitivity to bortezomib, the plasma compartment, with more than 90% cleared within 15
suggesting that the active requirement for protein folding in the ER minutes of IV administration. In whole-body autoradiography of
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provides a direct target and explains sensitivity to proteasome inhibi- [ C] bortezomib-treated rats, the CNS, testes, and eyes appeared to
tion. It also suggests a selective mechanism that could explain the be protected from bortezomib. Bortezomib specifically and selectively
emergence of less differentiated myeloma cells with decreased immu- inhibits proteasome function by binding tightly (dissociation constant
noglobulin production during treatment. These processes also increase [K i ] >0.6 nM) and reversibly to the enzyme’s chymotrypsin-like site.
oxidative stress and contribute to apoptotic signaling, explaining the In ex vivo 20S proteasome activity bioassays, the proteasome was
sensitivity of myeloma cells to proteasome inhibition. inhibited within 1 hour of bortezomib administration, and baseline
proteasome activity was restored within 48–72 hours. An intermittent
Preclinical Studies With Bortezomib but high level of inhibition (>70%) of proteasome activity was better
Screening of the NCI tumor cell lines revealed that bortezomib is tolerated than sustained inhibition. Thus, a twice-weekly clinical
active against a broad range of tumor types. The average growth dosing regimen is better tolerated. Nonetheless, this dose schedule
inhibition of 50% (GI 50) across the entire NCI cell panel (60 human- is often associated with significant myelosuppression and the onset
derived cell lines) occurred at 7 nM. Among solid tumor cell lines, of peripheral neuropathy. Reducing the dose schedule to a weekly
those of the prostate, breast, colon, and pancreas were exquisitely regimen ameliorates these toxicities and appears to increase patient
sensitive to proteasomal inhibition. PC-3 prostate carcinoma cells, tolerance without jeopardizing clinical efficacy.
treated with bortezomib, underwent growth arrest in G2-M phase
with a parallel increase in P21 levels and decreased activity, but not Clinical Studies With Bortezomib
the levels of CDK-4. Bortezomib treatment also led to caspase activa- Phase II clinical trials (11 years ago) with bortezomib demonstrated
tion, PARP cleavage, and apoptotic cell death with an IC 50 of 20 nM. the effectiveness of this agent in relapsed/refractory MM were
Bortezomib exhibited synergistic effects when combined with SN-38 reported. In the SUMMIT study of 202 patients with relapsed MM,
and radiation against colon tumor cells and in mouse xenografts. 27% of patients achieved a PR or complete response (CR), and
Similarly, pancreatic tumor xenografts were sensitive to the cytotoxic median time to progression was 7 months. The FDA approved the
effect of bortezomib, particularly when combined with gemcitabine drug for use in relapsed/refractory MM in 2003 on the basis of this
or CPT-11. Cytotoxic activity was reported as well against Lewis lung study. In 2008, the VISTA trial presented evidence demonstrating
carcinoma cells and nasopharyngeal squamous cell carcinoma cells. the superiority of bortezomib plus melphalan and prednisone (VMP)
In most of these studies, an increase in the cellular levels of P21WAF1, compared to MP alone for patients with newly diagnosed MM,
P27KIP1, P53, and IκB was observed. which led to FDA approval for the use of bortezomib combinations
In hematologic malignancies, proteasome inhibitors exhibited as front-line therapy. In the VISTA trial, the median TTP was 24
cytotoxic activity in a wide range of cell lines, including MM, U937 months for VMP versus 16.6 months with MP. After initial treat-
human monocytic leukemia, HL-60 promyelocytic leukemia, Jurkat ment, many patients remain sensitive to bortezomib and can be
T-cell leukemia, K562 CML, Ramos Burkitt lymphoma, and primary retreated upon relapse; 63% of patients who responded to initial
B-cell CLL. In MM cells, bortezomib induced p53 and MDM2 treatment with bortezomib respond to retreatment, with a median
protein expression, induced phosphorylation (Ser15) of p53 protein, TTP of 9.3 months. Bortezomib is also approved for the treatment
and activated JUN NH 2 -terminal kinase (JNK), which in turn acti- of relapsed MCL based on a demonstrated ORR of 33% in the phase
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vated caspase 8 and caspase 3. Bortezomib was also shown to activate II PINNACLE trial. Friedberg et al showed that the addition of
the intrinsic (mitochondria–cytochrome C [cyt c]–caspase 9) and bendamustine to bortezomib and rituximab (BVR) resulted in an
extrinsic (JNK–death receptor-activated caspase 8) apoptotic path- ORR of 83% with a 2-year PFS of 47% in patients with relapsed/
ways of the myeloma cells. Bortezomib blocked tumor necrosis factor refractory MCL. More recently, the results of the phase III LYM-
(TNF)-induced NFκB activation through inhibition of IκB degrada- 3002 trial were published where 487 adults with MCL ineligible
tion. TNF-induced intracellular adhesion molecule (ICAM)–1 for intensive therapy were randomized to R-CHOP vs VR-CAP
expression on RPMI8226 and MM.1S cells was also inhibited. The (replacing vincristine with bortezomib). The VR-CAP arms had a
unfolded protein response not only was increased in plasma cells median PFS of 24 months with a relative improvement of 59% over
producing large quantities of immunoglobulin, but also induced a the R-CHOP arm and 4-year OS was also better (64% vs. 54%).
stress apoptosis response. Bortezomib also induced osteoblast activity
through the Runx2/Cbfa2 pathway. Furthermore, bortezomib inhib-
ited receptor activator of NFκB ligand -induced osteoclastogenesis Second-Generation Proteasome Inhibitors
through inhibition of P38 kinase. Increased osteoblast activity has
the potential to restore the osteoporosis associated with MM when Carfilzomib: Carfilzomib is a second-generation proteasome inhibitor
used with or without bisphosphonates. Moreover, it prevented the that selectively inhibits the chymotrypsin-like activity of the protea-
adherence of myeloma cells to BM stromal cells and the NFκB- some and is active in bortezomib-resistant patients. Carfilzomib
dependent production of IL-6. Importantly, bortezomib demon- induces irreversible inhibition (once carfilzomib binds to its active
strated synergistic activity with dexamethasone, thalidomide, site within the barrel of the proteasome, the proteasome is perma-
melphalan, and doxorubicin and did not appear to be a substrate for nently inactivated and new proteasomes must be synthesized to
multidrug-resistance transporters. However, the NFκB blockade restore proteasome activity) compared with the reversible effects of
could not account for all of the antimyeloma activity of bortezomib, bortezomib (duration of proteasome inhibition lasts about 72 h).
and other mechanisms clearly contribute to its antineoplastic effects. Carfilzomib was approved in 2012 for the treatment of patients with
Finally, an IC 50 concentration of bortezomib in myeloma cells had myeloma who have received at least two prior therapies. As a mono-
no effect on peripheral blood mononuclear cells from healthy volun- therapy in phase II studies, carfilzomib induced an ORR of 20% in
teers and did not affect cultured BM stromal cells. This did not patients refractory to bortezomib. Carfilzomib appears to be less
preclude the observation of myelosuppression during treatment of likely to cause peripheral neuropathy, and is safe in patients with renal
patients with bortezomib as a single agent. impairment. Phase III studies of carfilzomib are ongoing. Higher