Page 967 - Hematology_ Basic Principles and Practice ( PDFDrive )

850 Part VII Hematologic Malignancies

lymphocytic leukemia (CLL), or maneuvers to overcome resistance applied to improve potency and specificity, solubility, kinetic profile,
of pretreated disease outside of cell-based therapies. However, as and tissue penetration and residence. For instance, to screen for a
predicted by the model, administration of these or other intensive kinase inhibitor, cells overexpressing an activated kinase may be used.
regimens in patients with relapsed or late-stage disease generally fails After an initial in vitro screen, human tumor cell activity is evaluated
because of a generalized resistance of tumor cells to all classes of using a series of athymic mouse xenograft studies targeting tumors
chemotherapeutic agents. from tissues that show promise in in vitro assays. More informative
data is generated from banks of patient-derived tumor cell lines,
often using Rho-associated kinase (ROCK) inhibition, and using
DEVELOPMENT OF CHEMOTHERAPEUTIC AGENTS patient-specific tumor xenografts for drug screening. These in vivo
models consist of primary malignancies grown in immunodeficient
The quest for anticancer agents for hematologic malignancies began mice, typically NSG mice. Some genetically engineer mice to express
with the nitrogen mustard class of compounds developed from needed human cytokines that promote leukemic cell growth, or
the chemical warfare agent sulfur mustard gas used in World War reconstitute mice with a human immune system to evaluate immu-
I. Since that time, the National Cancer Institute (NCI) and the nomodulatory drugs and cell-based immune responses. Another
pharmaceutical industry have developed complex approaches to drug model system mimics the human disease by establishing mice with
development, screening, and evaluation. Initial screening consisted specific chromosomal translocations and oncogene mutations found
of toxicity assessment against murine tumor cell lines. Currently, in human cancers. Drug efficacy endpoints are complex, since target
screening is directed toward numerous cell targets, including receptor effects may produce cell death, senescence, apoptosis, differentiation,
and downstream signaling kinases; inducers of cell death pathways, polyploidy, inhibition of metastasis, and loss of cancer stem cell
including those at the cell surface; mitochondrial enzymes; nuclear populations. Drugs with promising efficacy and novel mechanisms
DNA and DNA replication, processing and repair proteins, including of action then go on to formulation and toxicology testing, and are
base excision repair, PARP, CHK1, topoisomerases, and telomer- ultimately developed for phase I clinical testing through academic
ase; and inhibitors of histone deacetylase (HDAC) and histone centers, industry, or the NCI Cancer Therapy Evaluation Program.
methylation, cell cycle proteins, proteasomes, and the mitosis and Effective drug screening includes evidence of target effect specificity
spindle machinery. Therapeutic agents targeting microenvironment, and potency, consideration of effects across tumor types, recogni-
angiogenesis, and immune checkpoints round out the spectrum of tion of predictors of sensitivity and resistance that depend on the
therapeutic approaches. Whereas killing cells had been the backbone mechanism of action and known pathways of resistance, character-
of chemotherapeutic approaches to human malignancies, the field ization of genetic changes associated with resistance and acquired
of antineoplastic agent development, which in the first decade of resistance, and pharmacokinetic preclinical analysis. In all instances,
the 21st century was at a tipping point, has now embraced novel animal studies often fail to provide accurate prediction of thera-
targeted and highly effective compounds that block the function of peutic efficacy, pharmacokinetics, emergence of resistance, or even
specific kinases with surprising efficacy, even at late stages of disease. toxicities.
Ultimately a balanced approach is likely, with much more preci- Variants of patient-specific tumor xenograft (PDX) models, which
sion in drug selection, use of mechanism-based combinations, and allow for direct passage of human tumors in mice, include orthotopic
attention towards and anticipation of tumor heterogeneity, complex models that assess the tissue microenvironment for tumor growth and
subclonality, and emergence of predictable resistance patterns that drug efficacy, metastatic models that allow for removal of primary
dictate proactive drug selection and utilization. tumor and metastasis to the brain, lungs and bone, and direct
Examples include Bruton tyrosine kinase (Btk) and phosphati- implantation and metastasis, for instance into colon, spleen or
dylinositol 3-kinase (PI3K) inhibitors in lymphoid malignancies as marrow sites.
well as Janus kinase (JAK) inhibitors for treatment of myelofibrosis
and polycythemia vera. A number of differentiating agents, kinase
inhibitors, and immunomodulatory and cytostatic agents complete Phase I Clinical Trial Design
the antineoplastic armamentarium. The field of drug development
also has to contend with much more complex assessments of toxicities New anticancer agents are assessed through a series of clinical trials
due to both on- and off-target effects, as well as normal tissue effects. termed phase I, phase II, and phase III (Table 57.1). The purpose of
In the sections that follow these toxicities will be noted because they phase I clinical trials is to establish the safe and optimal biochemically
restrict the utility of many drugs and toxicities need to be monitored active dose of the compound in question with acceptable toxicity
when using new drug combinations. that can be used in disease-targeted phase II testing. During phase I
development, pharmacokinetics and pharmacodynamic measures are
Screening for Antitumor Activity Among studied in detail so that appreciable information can be forthcoming
from the very first set of patients targeted for treatment and to
Chemotherapeutic Agents allow confirmation of these observations in larger phase II disease-
focused trials. Dose schedule and route of administration are key
Identification of critical targets for therapy in cancer cells and the
microenvironment starts with the recognition of a known or novel
target that appears critical for cancer development, dormancy, growth,
or metastasis. The NCI Division of Cancer Treatment has a well TABLE Clinical Trial Design
molecularly characterized cell bank of malignancies that are available 57.1
for new drug screening. A more contemporary cell line resource is the
Cancer Cell Line Encyclopedia (CCLE), developed to assist in drug Phase I
analysis. It is a compilation of gene expression, chromosomal copy Evaluate safety by dose escalation and multiple dose schedules
number, DNA sequence, and RNA data from 947 human cancer Establish maximum tolerated dose and dose-limiting toxicity
cell lines collected across databases and repositories. Many cell lines Consider use of hematopoietic support if myelosuppression is dose
have drug sensitivity profiles from more than 20 anticancer drugs. limiting
Both academia and pharma utilize high-throughput gene knockdown Phase II
(shRNA and siRNA) library approaches, drug screening using large Establish response (complete, partial, objective) in specific diseases
compound libraries, and in silico screening based on protein and Phase III
drug structures for docking analysis. Repurposed drugs that are FDA Compare new treatment with established regimen for the disease in
approved or for which there are extensive data provide a rich resource randomized trials
for lead compound identification. Medicinal chemistry can then be