Page 995 - Hematology_ Basic Principles and Practice ( PDFDrive )

878 Part VII Hematologic Malignancies

suggests that increases in expression of components of the IL-2R upregulated in cancer cells, making ribosomal function and protein
can be achieved by retinoids and rexinoids, which may enhance the synthesis a potential therapeutic target.
cytotoxicity of DD. A phase I trial investigating the use of bexaro- Protein translation is divided into three phases: initiation, elonga-
tene in conjunction with DD in patients with relapsed or refractory tion, and termination. As discussed in earlier sections of this chapter,
CTCL was undertaken, and eight out of 12 treated patients showed mTOR inhibitors disrupt the initiation phase by preventing assembly
a greater than 50% increase in CD25 expression after treatment with of the eIF4F complex, responsible for ribosomal recruitment. Other
bexarotene. A phase II trial of DD demonstrated an ORR of 48% agents aimed at impeding translation by directly targeting the func-
in relapsed/refractory PTCL (excluding CTCL) with median PFS of tion of eIF4F have not yet had successful clinical applications.
+
6 months. Higher responses (61%) were seen in CD25 tumors. In
a phase II trial in patients with relapsed/refractory NHL, the ORR
−
+
was 25%, with similar responses in CD25 and CD25 tumors. Omacetaxine
DD has also demonstrated promising activity in 30 patients with
steroid-refractory acute GVHD, with 71% of patients responding Omacetaxine mepesuccinate (homoharringtonine, HHT, synribo), is
with either complete (50%) or partial resolution (21%) of GVHD. a semisynthetic, highly purified compound derived from a plant
Hepatic transaminase elevation was the dose-limiting toxicity. alkaloid discovered more than 40 years ago. Omacetaxine prevents
peptide elongation by binding the A site in the peptidyl cleft of the
large ribosomal subunit, thus blocking correct positioning of the
Heat Shock Protein Inhibitors amino-acid side chains of tRNAs. The clinical activity of omacetaxine
has been correlated with its capacity to decrease translation of short-
Heat shock proteins (HSPs) are molecular chaperones that increase lived proteins such as c-Myc, MCL-1, and Cyclin D1. The initial
their expression in response to cellular stresses, including heat shock, clinical studies of omacetaxine in CML were done with IV adminis-
nutrient deprivation, oxidative stresses, heavy metals, and alcohol tration, before the introduction of BCR-ABL inhibitors, and were
exposure. They form multimolecular complexes with cellular proteins focused on patients who had failed IFN-α. Interest decreased after
(called clients), regulating their correct folding, repair, degradation, and approval of imatinib for CML, but subsequent studies focused on the
function. A number of multigene families of HSPs exist, and their use of SC omacetaxine in patients who developed resistance to TK
individual products vary in cellular expression, function, and localiza- inhibitors and those carrying the T315I mutation. The maximum
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tion; they are classified according to their molecular weight (e.g., tolerated dose was 1.25 mg/m subcutaneously twice daily. Subse-
HSP90, HSP70, HSP27). Exceptions to this rule are the chaperones quent studies demonstrated omacetaxine was capable of achieving
identified as glucose-regulated proteins (GRP94 and GRP75). major cytogenetic response in 23% of chronic-phase CML patients
2
HSP90 is one such molecular chaperone that regulates the func- carrying the T315I mutation. Omacetaxine dosing was 1.25 mg/m
tion and stability of more than 200 proteins, many essential for twice daily for 14 days every 28 days until achievement of a hema-
maintaining cell signaling and survival during stress states. The tologic response, after which maintenance was given at the same dose
protective actions of HSP90 also allow cancer cells to escape the for 7 days every 28 days. Hematologic toxicity was frequent (neutro-
inherent toxicity of their environment, evade the effects of chemo- penia 44%, anemia 39%, and thrombocytopenia 76%), particularly
therapy, and protect themselves from their own genetic instability. In in the initial stages of treatment, and was managed by reducing the
humans, HSP90 consists of four genes, cytosolic HSP90α and number of days of drug administration. The most common nonhe-
HSP90β, GRP94, and HSP75/TNF-associated protein 1 (TRAP1). matologic toxicities were infections, diarrhea, nausea, and fever.
The monomer HSP90 consists of a conserved 25-kDa N-terminal Severe nonhematologic toxicities included infection (10%), fatigue
and a 55-kDa C-terminal domain. The N-terminus contains a highly (5%), and increased alanine aminotransferase (3%). Omacetaxine
conserved ATP-binding domain. Dimerization of these nucleotide- received FDA approval in 2012 for the treatment of CML patients
binding domains is essential for chaperone actions, ATP binding and who have failed two or more TKI treatments.
hydrolysis. Phosphorylation leads HSP90 to interact with
co-chaperones such as HSP70 and p23 to form heteroprotein com-
plexes, which are essential for interaction with protein clients, includ- DRUG RESISTANCE TO CHEMOTHERAPEUTIC AGENTS
ing protein kinases, transcription factors (e.g., steroid hormone OR MULTIDRUG RESISTANCE
receptor, retinoid receptors, and HIF-1α), and other proteins with
various functions (e.g., mutant p53, the catalytic subunit of telomer- Although many hematologic malignancies develop resistance to a
ase hTERT, TNFR1, and Rb). HSP90 inhibition leads to misfolded specific class of chemotherapeutic agents, especially to targeted thera-
client proteins that are involved in malignancy to be polyubiqui- peutics, through the development of kinase region point mutations,
tinated and degraded by proteosomes. emergence of resistance to multiple cytotoxic chemotherapeutic
The first generation of HSP90 inhibitors, benzoquinone ansamy- agents is also common among hematologic malignancies. The basis
cins (herbamycin A, geldanamycin, and tanespimycin) was observed for resistance includes specific drug resistance mechanisms, overex-
to have some antineoplastic activity, but their clinical development pression of the ATP-binding cassette (ABC) transporters such as
was limited by difficulties in formulation, hepatotoxicity and MDR-1 for drug efflux, and overexpression of antiapoptotic proteins.
unexpected deaths in clinical trials. Newer, nongeldanamycin agents The Goldie-Coldman hypothesis predicts that drug-resistant tumor
have improved bioavailability and water solubility, and have been cell clones survive because of a favorable spontaneous mutation,
observed to have limited single-agent activity against hematologic which occurs in approximately one in a million cells. Because 1 g of
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malignancies. In phase I studies in lymphoid malignancies, the tumor contains 1 × 10 cells, it becomes obvious that high tumor
HSP90 inhibitor AUY922 had an overall response of 10%, and was burden states contain cells with a tremendous number of mutations,
associated with grade 3 fatigue, visual disturbances, and anemia. With which can contribute to drug resistance. This is the rationale for using
data suggesting possible synergy with other antineoplastic agents, combination chemotherapy at specific dose intervals to maximize
it is possible that HSP90 inhibitors may be used in combination dose intensity.
strategies. Drug-resistance mechanisms have been discovered and subse-
quently defined at the molecular level by investigators working in
vitro with tumor cell lines selected in the presence of specific antitu-
Protein Translation Inhibitors mor agents, by analysis of primary samples of untreated and treated
hematologic malignancies, and through screening of tumor banks.
The increased proliferation and cell survival of cancer cells imposes Classes of resistance include acquired protein deficiency, loss of sen-
a requirement for increased levels of short-lived proteins involved in sitivity to apoptotic signals, and age-related defects in the cellular
cell division and survival. As a result, protein translation is markedly pathways that normally lead to apoptosis.