Summary SSA16 Development and use of small molecule therapeutics
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Course
Molecular Biology And Oncology (311300130Y)
Institution
Universiteit Leiden (UL)
Summary and WG answers of SSA16 Development and use of small molecule therapeutics of the course MBO (molecular biology and oncology) at Leiden University.
SSA16 Development and use of small
molecule therapeutics
Chapter 16 Weinberg
The incidence of cancer of the years cannot be really compared due to changes in detection
technology.
16.1 The development and clinical use of effective therapies
will depend on accurate diagnosis of disease
The traditional way of classifying tumors based on their origin and morphology now has
limited utility. More important is the underlying nature of the tumor and the chance of such a
tumor to respond to therapy. Cancer is not one disease, but it has many subcategories.
All tumors (except skin cancer) are treated very aggressively in order to reduce as much as
possible the chance that it progresses and becomes life-threatening. Would like to target this
type of therapy more by predicting this actual chance.
Indolent tumors have low invasive and metastatic potential and remain in such a state
Not worthy of treatment. Treatment/surgery too harmful for the benefit
Highly aggressive tumors with high chance to metastasize are likely to have
disseminated by the time the primary tumor is diagnosed Questionable whether it
is worthy of treatment as truly effective treatments for metastasis do not exist.
Tumors of intermediate grade have potential to disseminate but can be excised or
treated before this to prevent life-threatening metastasis Treatment most likely to
give benefit as it can prevent metastatic spread
Some forms of common chemotherapies are alkylating agents or DNA modifying agents.
Although effective for some tumors, they can also increase the risk of acute myelogenous
leukemia (AML) because the drugs have mutagenic actions.
For various types of cancer, treatment will not lower the frequency of formation of life-
threatening carcinomas. Even for invasive breast carcinomas, most are unlikely to cause
death, even when left untreated. This shows that it is really necessary to develop molecular
markers that enable to distinguish between tumors that really should be treated aggressively
and those that just need to be monitored for progression.
Gene expression arrays (functional genomics) allow to stratify cancers. Bioinformatics make
it possible to identify a subset of genes whose expression is correlated to a biological
phenotype, drug responsiveness and/or prognosis.
Traditionally, the main prognostic parameters for breast cancer were age, tumor size,
affected lymph nodes, histological type, pathological grade, receptor status. However, this is
not accurate. More patients are classified to be treated aggressively than actually needed.
Gene expression arrays and bioinformatics allowed to predict prognosis with 90% accuracy.
Differentiation programs work together with somatic mutations and epigenetic alterations to
dictate the cancer cell phenotype and also responsiveness to therapy. There is thus a
complex interaction between genetics and non-genetics. Cancer cell behavior can therefore
, not be predicted with sequencing alone. Protein expression would be the best to measure,
but this is still too difficult. Therefore we use gene expression arrays.
Gene expression arrays also allowed to separate B-cell lymphomas into three separate
diseases. Activated B cell lymphoma (ABC) and primary mediastinal B cell lymphomas
(PMBLs) have high NFkB activity. This transcription factors drives their proliferation and
protects them from apoptosis. Drug target is then IKK which is an upstream activator. The
third type, germinal center B-cell-like lymphoma does not have this increased NFkB activity
and thus also does not respond to IKK treatment.
Gene expression arrays are often confounded by the fact that the tumor is heterogeneous
and also consists of normal stromal cells. Laser capture microdissection (LCM) makes it
possible to isolate the actual carcinoma cells from the stroma to analyze the gene expression
profiles separately so that the analysis is refined and more accurate. Recently it also became
possible to analyze the transcriptome of a single cell. This can be done by sequencing all
mRNAs by first making them into cDNA with reverse transcriptase. Proteomics are even
more promising.
16.2 Surgery, radiotherapy, and chemotherapy are the major
pillar on which current cancer therapies rest
Although these older treatments do not have a really good rationale, they seem to be very
effective. New treatments are often more rational agents. Adjuvant is post-surgical therapy.
Evidence based medicine showed that surgery is not always a good option to prevent cancer
progression. Radiotherapy has improved as the rays are now only directed in a more narrow
field where the tumor is to make sure the surrounding tissue is not damaged too much. There
are now also drugs coupled to radioactive isotopes to get the radiation more locally.
Most cancer therapies like radiotherapy and chemotherapy are also cytotoxic to normal cells
and can even be carcinogenic as they often have mutagenic actions. Antimetabolites
interfere with the normal functioning of specific metabolites or enzymes in cells. Often the
targets are involved in the DNA synthesis. Another form of antimetabolites are molecules
interfering with the microtubule assembly. They can break down microtubules or can be
depolymerizing to prevent assembly. Colcemide can trap cells in mitosis. Alkylating agents
induce covalent modifications of the DNA and create adducts that cannot readily be removed
by the cells repair machinery. Cisplatin generates intra-strand cross-links.
Questions: (1) How do these cytotoxic drugs kill cancer cells? (2) Why do they kill cancer
cells more readily than normal cells? (3) How do cancer cells become resistant to them?
Selectivity; Cytotoxic drugs kill proliferating cells. Can also selectively target cells with a
certain defect in repair, detoxification or response mechanisms.
Due to the development of resistance, there are now multi-drug protocols in which a
complementary combination of drugs is used. Often antimetabolite, alkylating and
microtubule antagonist agents. Hematopoietic malignancies seem to respond well to such
protocols, but solid tumors less. Resistant populations arise more frequently than would be
expected. The cells have multi-drug resistance and these cells often have membrane drug
pumps. The resistance of apoptosis also leads to some resistance to these drugs. Can also
become resistant by detoxifying the drug or activate a compensatory mechanism.
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