Introduction to targeted drugs for Lymphoma
Desirable binding sites for a drug are those that
inhibit a pathway
abnormal growth and survival
malignant cells and have fewer
You can click the image to open an illustration of
pathways within the b-cells to appreciate the complexity of cell biology
Briefly, a cancer develops from
genomic damage (mutations) to
cells that lead to the abnormal growth and persistence of the cells
The mutations can lead to epigenomic changes
that turn on or off specialized genes that would protect the cell
becoming a cancer (such as tumor suppressor genes) or being detected by the immune system
(such as immune checkpoint blockade).
Here's an introduction to the mechanisms of action for targeted drugs
that can lead to more selective killing of cancer cells:
inhibiting pathways inside the tumor cell
that are activated by the mutations
-- driving the malignant behavior of the tumor cells. Many
of these are small molecule drugs taken orally (such as
Study drug names of this type end with "NIB" or "TIB"
There are many kinds of pathways and binding points within a
pathway. Many pathways are involved in the transcription
of genes -- making proteins that promote cell growth. Some
pathways silence genes that protect against uncontrolled cell
growth; other pathways may help to hide the tumor cell
from the immune system or inhibit immune function.
activating genes that have been silenced,
or turning off over-active genes. Sometimes called epigenetic
HDAC inhibitors or
Many of these study drug names end with "STAT"
binding to surface
antigens that are expressed on the
surface of the type of cell, such as cd19, cd20, cd22, cd30 ...
- by binding - activating signals within b-cell (Rituxan)
- by inducing immunity against the bound cell
- by delivering a toxin (antibody-drug conjugate)
- by delivering radiation (radioimmunotherapy)
Note: Monoclonal antibodies (proteins that stick to antigens)
is the most common class of therapy used to target cell surface
Antibody drug names end with "MAB" (such as Rituximab)
by inhibiting how the cancer cells "hijack" the host system, such
as the immune system (immune checkpoints) or the blood supply
(angiogenesis). May also be described as immune
with adoptive immunotherapy -
by infusions of immune cells harvested "or adopted" from a donor or the patient ...
that are primed or engineered to target malignant cells (e.g., CART 19, allogeneic stem cell transplant)
by damaging rapidly dividing
cells (cytotoxic) - inducing cell death (apoptosis) - a
So targeted drugs can work in many
different ways - commonly by interfering with a pathway
inside or outside the cell that
supports the abnormal growth or persistence of the lymphoma cells.
What are cell pathways? An analogy: the electrical and fuel systems of an automobile might be called pathways
that control how fast or slow an engine runs. Similar to how a faulty fuel
system can cause an engine to race ahead, a faulty pathway in the
cells can cause the cells to grow too fast or to resist cell death.
The activity of a cell pathway can be inhibited by a drug when it binds to the part of
the cell that supports the cell activity - similar to how a mechanic
must turn a specific screw to change the fuel-air mixture to modify
how fast an engine runs.
Targeted drugs may also bind to parts of normal cells that permit malignant behavior -- sometimes
referred to as the tumor microenvironment. Immune checkpoint
antibodies are examples of agents that target pathways that help the
abnormal cells escape the immune system.
The binding of the drug to the cell is similar to how a key will
fit only one kind of lock. Desirable binding sites for a drug are
those that can interrupt or turn off a pathway that promotes
abnormal cell growth and survival in the malignant cells. The
best targeted drugs fit the target with high affinity and
bind to few off-target, normal cells.
Effective targeted drugs may also activate (turn on) pathways that
help the cell to self-destruct. This would be similar to an intervention by a mechanic that
turns on the breaking system allowing the automobile to stop
normally. Other targeted drugs may shut down the signals from the tumor
cells that stop an attack by the immune system.
An active drug inhibits or activates a pathway that causes
tumor cells to die. The activity might be determine in cell culture
or animal models. An effective drug achieves this with
acceptable side effects - leading to the patient living longer and or better
(clinical benefit). The goal of early phases of clinical
research is to identify a safe dose that shows activity against the
disease (the therapeutic window). The later phases are done to see if the active dose
is also effective - provides meaningful clinical benefit.
The binding sites for the drug on the cell may be highly specific to the tumor
cells (not found on any other cell) or they may be expressed (turned
on) in a limited type of normal cells, such as only on mature
In general, the higher the specificity of the drug to the tumor, the
fewer kinds of side effects (off-target effects) there will be.
However, the significance of the off-target effects depends on the
type of cells that are affected: heart
cell versus skin cell, for example.
For lymphoma there are numerous study drug targets as our
work-in-progress shows (right panel). A well-known proven example is
CD20, the binding site of Rituximab, which is found only on the
surface of mature b-cells. After therapy that eradicates mature
b-cells, these normal cells can emerge from the immature b-cells that the
drug did not stick to.
Notably, some targeted therapies may kill
lymphoma cells indirectly by eliciting an immune response. The binding of the drug to the cell
acts like a flag attracting immune cells that then kill the cells.
One reason for optimism that progress against lymphoma will
continue is the number of targets that are specific to mature
b-cells that can be targeted in this way; another is the high
sensitivity of lymphoma cells to regular (chemotherapy and
Some targeted drugs have already been proven to be effective in the
treatment of lymphoma, such as Rituximab. However, testing is needed
for each new agent. That a new drug is "targeted" does not mean it
will also prove to be more effective or safer than regular
treatments for lymphoma.
Please note: regular therapies can be very effective
against lymphoma. Indeed, in more than one type of lymphoma cytotoxic chemotherapy is curative and adding immunotherapy has
improved outcomes further (Rituxan with chemotherapy). While single and multi-drug combinations
of targeted drugs may eliminate the need for chemotherapy one day,
the most effective use of targeted agents may be when used
concurrently, or in sequence, with
Progress is not possible without patients willing to take part in
clinical trials. Fortunately, there are many situations where
taking part in such studies makes good sense and compete well with
regular treatments as described here.
to Consider Trials based on
our unique clinical circumstances
Since choosing a trial is complicated, we believe it's important
also to consult specialists. To assist we provide:
- specialists to consult about trials
Cancer cells have many complex pathways that can be targeted by
different kinds (or classes) of therapies. For example,
there are perhaps many dozens of cytotoxic agents that target cancer
damaging the DNA of rapidly dividing cells (commonly called
We are now in an era of developing other classes of
agents that can augment or replace cytotoxic agents by targeting other
pathways that can directly or indirectly enhance the more selective
killing of cancer cells.
Antibodies - about
Targets proteins on
the surface of normal mature b-cells, such as cd20 (Rituxan)
Pathways: triggers the death of the cells it binds to
directly; elicits or calls an immune response
Find Trials for this
type of agent
Targets pathways inside the cell that
prevent programmed cell death (apoptosis)
Cancer cells and resistance of cancer cells to treatment are
thought to be caused by
"defects in the apoptotic pathway"
Trials for this type of agent
Target a pathway
inside the cell that prevents programmed cell death.
This particular kinase is related to the function of the b-cell receptor on
||Activating tumor suppressor
genes (coming soon)
* Andrew Wolf: On role of tumor suppressor genes in cancer
||2006: Tumor suppressor gene
methylation in follicular lymphoma: a comprehensive review”
Snips: "Tumor suppressor genes function by one of the
following mechanisms: protect the genome from mutagenic events,
impede dysregulated progression through the cell cycle, induce
apoptosis in cells that escape normal cell cycle controls, and
inhibit cellular migration and metastasis."
In the future, four unique settings exist to investigate
hypomethylating agents in FL: i. refractory disease; ii.
transformed lymphoma; iii. alternative to traditional cytotoxic
chemotherapy; iv. adjuvant to induction cytotoxic chemotherapy.
Patients with refractory cancers are often considered for early
development trials as they have already failed standard
therapies. Given lymphoma patients short duration of response in
phase I trials of DNMT inhibitors, we expect DNMT inhibitors
will be most active when incorporated into a multi-drug regimen.
Additionally, FL transformation is associated with aberrant
methylation of cyclin dependent kinase inhibitors and
therapeutic reversal should be explored in this setting. Another
appealing strategy is to treat FL patients without cytotoxic
therapies. If the hypomethylating agents can induce the
expression of androgen receptor, DAPK, and IL-12 receptor β-2,
then concurrent treatment with their respective ligands may be
investigated clinically. Finally, if a clinical benefit is
demonstrated in these settings, DNMT inhibitors could be
evaluated as an adjuvant to FL induction chemotherapy regimens.
SHP1, also known as PTP1C, PTPN6, HCP, and SHPTP1, is a
phosphotyrosine phosphatase that plays many important roles in
regulating immune system cell differentiation and activation
DNA promoter hypermethylation of the androgen receptor gene is a
common finding in FL and other lymphomas.
Methylation of DAPK may be a common epigenetic event in
FL. In two published studies, twenty-five of twenty-nine (86%)
FL samples were positive for aberrant DAPK methylation
The loss of p16 activity, either through gene mutation or
promoter hypermethylation, is a common step in tumor development
In a recent study, eight of eighteen FL samples (44%) had
methylation of the p57 promoter region .
A similar proportion of p57 methylation is found in
diffuse large B-cell lymphoma samples
IL-12 may serve as a tumor suppressor across a wide variety of B
cell malignancies and methylation of IL-12 receptor β-2 gene may
be a common step in the development of B cell malignancies.
epigenetic agents, epigenetic agents