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Treatment Overview > Agents that Target Disease Pathways

Last update: 01/05/2018

Introduction and background

Agents-index | By Class | Immunotherapies |
Terms 
It's important to emphasize that lymphomas (blood cell cancers) are typically highly sensitive to standard chemotherapy and radiotherapy, which work by damaging the DNA of rapidly dividing cells -- inducing apoptosis (programmed cell death), which is similar to what skin cells do when exposed to too much sun (peel off).  

By definition, study drugs need to be tested for safety and efficacy.  Some of these may* help to manage the disease better with less toxicity, or when the lymphoma becomes resistant to usual treatments, or they may help to improve the duration of response when added to usual treatments.  Some of these agents may prove to be best when used before, with, or just after standard therapies to potentially improve outcomes.  "
May" is the operative word.  By definition a clinical trial is done to test a study concept.

When to consider trials studies these agents? 
How best to proceed? 
7 Reasons to Consider Trials based on our unique clinical circumstances
Trial Talk - specialists to consult about trials
 

Here our goal is to foster a general understanding of how targeted agents for lymphoma are thought to work -- as an aid to better informed decision-making when considering clinical trials. The alphabetical index of targeted study drugs can also be used by medical professionals to easily locate clinical trials that may be appropriate* for their patients -- a good match based on the patient's clinical needs and treatment goals.

Introduction to targeted drugs for Lymphoma

Desirable binding sites for a drug are those that inhibit a pathway that promotes the abnormal growth and survival of the malignant cells and have fewer off-target effects

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 (malignant behavior). 

The mutations can lead to epigenomic changes that turn on or off specialized genes that would protect the cell from
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:

by 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 ibrutinib)

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.

by
activating genes that have been silenced, or turning off over-active genes.  Sometimes called epigenetic agents (
such as HDAC inhibitors or Abexinostat) 

Many of these study drug names end with "STAT"

by
binding to surface antigens that are expressed on the surface of the type of cell,  such as cd19, cd20, cd22, cd30 ...  on lymphocytes
- 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 antigens. 

Antibody drug names end with "MAB" (such as Rituxi
mab)

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 modulating drugs.

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 standard approach.

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 b-cells.

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 radiotherapy) therapies.

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 regular therapy.

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. 

 7 Reasons 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:

Trial Talk - specialists to consult about trials

Targeted Agents by Category or Mechanistic class:

Antibodies | Antibody-drug conjugates | Antibody-radiation conjugates | Apoptosis - targeting |  Btk-inhibitors (ibrutinib) | Engineered T-cells (CARS) | Epigenetic therapy - HDAC inhibitors |  Immune Checkpoint Blockade | Lenalidomide |
PI 3K kinases (Idelalisib)  AND ...  In the News 

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 cells by damaging the DNA of rapidly dividing cells (commonly called chemotherapy). 

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.

Targeted Agents

For reports and to find trials for targeted agents:

* Find Clinical Trials by Type of Treatment Agent

* Also see:  Anticancer Agents - My Cancer Genome http://bit.ly/1powkfa

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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
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Antibody-drug conjugates 

Find trials for this type of agent

Targets proteins on the surface of normal mature b-cells
Delivers toxins or chemotherapy to the targeted cells
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Antibody-radio-isotope conjugates - radioimmunotherapy

Find trials for this type of agent

Targets proteins on the surface of normal mature b-cells
Delivers radiation to the targeted cells

See also
About radioimmunotherapy
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BCL-2 inhibitors  (coming soon)

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"
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Btk-inhibitors  About

Find 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 mature b-cells

 
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Engineered T-cells:  Chimeric Antigen receptors that target CD19 (CAR19 t-cells/CTL019)

See
Programming T-cells to work like antibodies
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HDAC inhibitors:  About | Find Trials
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Immune Checkpoint Blockade
bullet
Immune modulating agent: Lenalidomide

Targets cells in the tumor microenvironment
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PI 3K kinases
bullet Activating tumor suppressor genes  (coming soon)
* Andrew Wolf:  On role of tumor suppressor genes in cancer 
 
bullet 2006: Tumor suppressor gene methylation in follicular lymphoma: a comprehensive review” http://1.usa.gov/1uCiK6I

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 and progression.

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

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Exploring Precision Cancer Medicine for Sarcoma and Rare Cancers (2013-2017) | CBSSM http://bit.ly/1Edel0E
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ASCO Post: “Novel Agents Show Activity in relapsed Non-Hodgkin Lymphoma”  including CRs http://bit.ly/1dSn1gv
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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
 
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The Hematologist: Inhibition of B-Cell Receptor Signaling as a Therapeutic Strategy for Treatment of CLL  http://bit.ly/12zzCfN
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Biomarkers
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The Hematologist: All in the Family: Fine Tuning Targeted Attack on BCL-2
bullet "BET family has a pivotal role in regulating the transcription of growth-promoting genes” http://1.usa.gov/1Q7vWyI
 
bullet The Eph-Receptor A7 Is a Soluble Tumor Suppressor for Follicular Lymphoma: Cell http://bit.ly/1jAyorL

 

 
 
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