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 few
You can click the image to open an illustration of
pathways within the b-cells -
and to appreciate the complexity of human biology
Our goal is to foster a general understanding of how targeted agents for lymphoma are thought to work as an aid to
informed decision-making when considering clinical trials.
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).
It's important to note that lymphoma is highly sensitive to
standard cytotoxic chemotherapy and radiotherapy, which work by damaging the DNA
of rapidly dividing cells causing the cells to initiate programmed cell
may work with or sometimes replace
standard treatments. They can be used before, with, or just after
standard cytotoxic therapies to improve outcomes.
Mechanisms of action for targeted drugs:
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
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
4) by 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)
5) 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
6) with adoptive immunotherapy -
by infusions of immune cells adopted from a donor or the patient ...
that are primed or engineered to target malignant cells (e.g., CART 19,
allogeneic stem cell transplant)
7) 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 the cell or outside the cell that
supports the growth or persistence of the abnormal cells.
The electrical and fuel systems of an automobile might be called pathways
that control how fast or slow an engine runs. Just as 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.
A cell pathway can be modified 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.
The binding sites of targeted drugs may be on the cell surface or
inside of the cells. Targeted drugs may also bind to normal
bystander cells that promote malignant behavior -- sometimes
referred to as the tumor microenvironment.
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.
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 prevent signals from the tumor
cells that shut down an attack by the immune system.
An active drug inhibits or activates a pathway that causes
tumor cells to die. 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 find a safe dose that shows activity against the
disease. 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 many promising targets for cancer dugs
that bind to and kill only mature b-cells. A well-known example is
CD20, the binding site of Rituxan, which is found only on the
surface of mature b-cells. After therapy that eradicates mature
b-cells, these cells can emerge from the immature b-cells that the
drug did not stick to.
Notably, some targeted therapies, such as antibodies, 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 Rituxan. 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.
It's important to note that 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
Targeted agents may also be used before regular treatment (as
"priming" therapy) with or after regular treatment (as consolidation or
maintenance therapy) to improve the quality and duration of the
response to treatment.
Targeted Agents by Class:
Apoptosis - targeting |
Epigenetic therapy -
Immune Checkpoint Blockade |
PI 3K kinases (Idelalisib) AND ...
For reports and to find trials for targeted agents:
Clinical Trials by Type of Treatment Agent
* Also see: Anticancer Agents - My Cancer Genome
Antibodies - about by PAL
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"
Btk-inhibitors About by
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
In the News and Related Resources
Exploring Precision Cancer Medicine for Sarcoma and Rare
Cancers (2013-2017) | CBSSM
ASCO Post: “Novel Agents Show Activity in relapsed
Medscape: The Current Status and Future Impact of Targeted
Therapies in Non-Hodgkin Lymphoma http://bit.ly/13wa3eE
Chaitra Ujjani, MD; Bruce D. Cheson, MD
The Hematologist: Inhibition of B-Cell Receptor Signaling as
a Therapeutic Strategy for Treatment of CLL http://bit.ly/12zzCfN
||"BET family has a pivotal
role in regulating the transcription of growth-promoting genes”
||The Eph-Receptor A7 Is a Soluble
Tumor Suppressor for Follicular Lymphoma: Cell
||EPZ-6438 ((EZH2 Histone Methyl
Transferase [HMT] Inhibitor)
||G100 toll-like receptor 4 (TLR4)
||PF-05082566, a 4-1BB agonist
monoclonal antibody (mAb)
||Cytochrome P450 (CYP) 3A inhibitor
(erythromycin) and a strong CYP3A inhibitor (voriconazole)
New Trials of interest
Alphabetical Index of Targeted Agents for lymphoma
Based on trials, promising
reports, and recent approvals
Study drug name 1 / alternate name
(short name for target or mechanism) 2
Find Trials 3
1 – shows background
2 – mechanism or target
3 – lists clinical trials for agent
Recently added agents are highlighted
Terms related to targeted therapies
The purpose is to
introduce terms used for targeted therapies for lymphoma
Cancer is caused by genetic abnormalities
or defects in genes called
Genes are recipes that our
cells follow to make cellular proteins.
These proteins lead to signals within the cell that determine
(or drive) the cell
... The signals involve many parts of the cell called
(Analogy: the electrical system in an automobile is similar to a
pathway; distinct from the fuel system.
Mutations in key genes
(oncogenes) can cause the affected cell to divide too rapidly
and/or to persist too long
This so-called malignant behavior, can lead to the accumulation
of the cancer cells called tumors.
effective targeted drug is one that binds to a molecule
of tumor cells leading to stopping the growth or tumor cell
For this reason targeted therapy is sometimes called
molecular or precision medicine.
The molecule or target that the drug binds to can be external
An external target is typically a
receptor that is on the surface of the cell that's unique
to the type of cell or tumor cell, such as cd20 in
An internal target is typically a molecule inside the
cell that is involved in a signaling pathway that is
overactive because of a mutation in the gene.
The best targeted drugs have good specificity
Specificity means the target is unique to the tumor cell.
Affinity means how well the drug binds and remains bound to the
target. A drug with high specificity will have less
off-target effects (side effects). A drug with high
affinity is more likely to be active against the disease.
Limitations and considerations
study drug is targeted
does not mean it will prove to be effective or safe for a given type
of lymphoma or cancer when tested in clinical trials.
Important questions for patients, and consideration for referring
1) Is the targeted agent first-in-class (never before tested in
has a similar agent proven effective in clinical tests in patients
with your type of lymphoma?
2) Is there is a companion diagnostic test to help determine if the
target exists based on your tumor sample.
molecular target might
vary leading to good or poor binding.
internal pathway might not
be driving the malignancy, or the tumor cells might adapt
leading to a limited activity against the behavior of the cells.
Or, the external receptor
might not be related to cell growth or survival.
targeted agent might have off-target effects
(binding to similar molecules on normal cells) leading to
targeted agent might not be safe or tolerable at a dose needed
to have anti-cancer effects.
Note: When testing targeted drugs that have been approved
in other types of cancer, the clinically active and safe dose
will be based on prior clinical experience. Therefore the
recommended dose and risks will be better understood and can be
monitored for with more assurance.
Other terms (coming soon)
Genes have different names, such as BRAF.
Oncogenes are genes that can lead to cancer when mutated. The
changes/ rearrangements / mutations to genes can take place in
different portions of the gene (codon, exon), leading to activation of
Most targeted drugs inhibit the pathway ...
do not correct the gene mutation.
The changes to genes leading to cancer are
almost always acquired (somatic), not inherited (germline).
cellular signal transduction
Recurrent mutations in exon NUMBER
of GENE NAME (eg. BRAF)
wild type MUTATION NAME (BRAF).
GENE NAME rearrangements
(mutations) fuse the kinase domain NAME with a partner gene
which leads to constitutive activation of the NAMED pathway