Targeted Therapies: A New Generation of Cancer Treatments

[RandyW]

This is a bit long and an indepth article on Targeted THerapies;

http://www.redorbit.com/news/health/128 ... reatments/

[jaminkw]

Randy: Yea, I made my way ploddingly through the article. I have to admit, I scanned a few paragraphs as I was most interested in my next therapy--maintenance Avastin.

Before I comment on the article, I have to insert a quote in response to a question I posted recently on onctalk.com. Dr West said: "I just wanted to chime in to say that I totally agree with Dr. Laskin here. 'Targeted therapy' is a nebulous term that people use to convey that they have some idea of what the treatment is supposed to be doing, but it's really just buzz-speak -- vague marketing to suggest that it's new and improved and not that old school chemo people used to have to take. Other experts have suggested that the definition of targeted therapy is any cancer treatment that has come out since about 2002.

We really shouldn't forget that chemo is targeted and radiation is targeted, even if the target is DNA and not "EGFR" or "VEGF" or some other molecule you've never heard of before. The quotes you mention sound like typical vague fluff about something pretty complex."

That out of the way, the article was interesting in that it did seem to try to strike a balance between benefit and hazard of the therapies reviewed. I have looked at Avastin (and particularly the maintenance use) from so many perspectives on the net and really don't find much that conflicts but neither does the info do much to help me make my personal decision. The risks are significant to me, particularly the possibility of heart attack or stroke if I can't get and keep my blood pressure under control. And the leap of faith required to do a treatment indefinitely that has only been suggested to slow down the cancer in one trial (that's all I can find), not randomized, and not with patients with lung cancer feels like a huge leap to me.

Judy in Key West

Thanks for the link cause I for one am not yet done digging into the pros and cons of cancer therapies!

Judy in Key West

[gpawelski]

Drug companies are betting on the future of "targeted" medicine, hoping to improve patient outcomes by using genetic tests to figure out which patients could benefit from a given drug.

The new paradigm of requiring a companion diagnostic as a condition for approval of new "targeted" therapies, the pressure is so great that the companion diagnostics they’ve approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies.

If you find one or more implicated genes in a patient’s tumor cells, how do you know if they are functional (is the encoded protein actually produced)? If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?

All cells exist in a state of dynamic tension in which several internal and external forces work with and against each other. Just detecting an amplified or deleted gene won’t tell you anything about protein interactions. Are you sure that you’ve identified every single gene that might influence sensitivity or resistance to a certain class of drug?

Assuming you resolve all of the preceeding issues, you’ll never be able to distinguish between susceptibility of the cell to different drugs in the same class. Nor can you tell anything about susceptibility to drug combinations. And what about external facts such as drug uptake into the cell?

Good luck doing this with genetic tests!

[jaminkw]

gdpawel: You're way over my head in detail but I get the general idea. Something tells me some people in the industry know it won't work but if they can convince the public (and the FDA?), oh well $$$$$$$$$ anyway.

Judy in Key West

[gpawelski]

Yeah, Judy. I am so use to researching and studying this stuff, I do have a hard time breaking it down. I apologize, but I try.

Cells are the most basic structure of the body. Cells make up tissues, and tissues make up organs, such as the lungs or liver. Each cell is surrounded by a membrane, a thin layer that separates the outside of the cell from the inside. For a cell to perform necessary functions for the body and respond to its surroundings, it needs to communicate with other cells in the body. Communication occurs through chemical messages. The purpose of these messages is to tell the cell what to do, such as when to grow, divide into two new cells, and then die.

The "targets" that the new smart drugs go after can be located on the "inside" or "outside" of a cancer cell. The most common targets on the outside are receptors, proteins that help relay chemical messages. The many targets on the inside are enzymes, proteins that help speed up chemical reactions in the body of the cell.

Basically, "targeted" cancer therapies use drugs that block the growth and spread of cancer by interfering with specific molecules (proteins) involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth.

The kinases act on and modify the activity of specific proteins. Iressa and Tarceva are very similar drugs, small molecule inhibitors of tyrosine kinase, a key intermediary in the EGF cascade pathway. In some cancer cells, EGFR triggers uncontrolled cell division.

So people will get some sort of gene-based test to measure the expression-mutation of these kinases. They test patients for EGFR to determine which patients would benefit from targeted therapies such as Iressa and Tarceva, which is limited only to those patients whose tumors are determined to be EGFR protein positive.

But something more elemental (sinister if you will) is going on. Does the drug even enter the cell? Once entered, does it immediately get metabolized or does it get pumped out. Some clones of cancerous tumor cells don't accumulate these drugs. These cancer cells won't get killed by it. There are rare patients that respond very well. However, cancer cells evolve resistance to Iressa or Tarceva by multiple mechanisms related to genetic alterations both within the EGFR gene and at other sites.

Targeted drugs like Iressa and Tarceva should be limited only to patients who would benefit from such drugs. Will the fact that EGFR negative patients not benefit from Tarceva and limit its usage? No. They could benefit. The FDA approved indication for Tarceva does not limit prescribing specifically to EGFR positive patients. The growth of lung cancer appears to depend upon a variety of different growth factors. If the growth of the tumor is not entirely dependent on EGFR, it may not be effective.

But you won't pick this up with an genetic assay which only measures the kinases themselves. The headlong rush to identify molecular (genetic) predisposing mechanisms (pathways) still does not guarentee that a drug will be effective for an individual patient. Nor can they, for any patient or even large groups of patients, discriminate the potential for clinical activity among different agents of the same class, such as Tarceva, Iressa, and Nexavar.

If there are a number of different influences on different tumors, then you must either isolate it very specifically, or use a variety of drugs to combat various methods of those influences. A cell-based "functional" assay can measure the net effect of everything which goes on. Are the cell ultimately killed, or aren't they?

"Functional" profiling (is the cell being killed regardless of the mechanism/pathway) assesses the activity of combinations of drugs, upon combined effect of "all" cellular processes, using several metabolic and morphologic endpoints. This, as opposed to gene profiling (does the cell express a particular target that the drug is supposed to be attacking).

While a "target" assay tells you whether or not to give "one" drug, a "functional" assay can find other compounds and combinations and can recommend them from the one assay. The concept is that you are better off using a drug that your tumor reacts to strongly than one your tumor resists.

Greg

[jaminkw]

Greg: So now I do think I understand the futility of developing the genetic or "targeted" assy. But what about the functional assy. Are we doing this now with scans or other testing methods, or is this still to be developed?

Judy in Key West

[gpawelski]

Judy, the "cell" is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one or a few targets or pathways.

First of all, what is a functional assay? It is actually a number of assays that correlate with each other. The DISC assay, the MTT assay, the ATP assay, the resazurin assay, and the caspase 3/7 assay. Basically, they have either morpholigic or metabolic endpoints. The Medicare-approved assays are the DISC, MTT and ATP, known as Oncologic in Vitro Chemoresponse Assays. In 2006, Medicare officially recognized these cancer assays as a special test category in Federal Regulations (42 CFR 414.510((3), 71 FR 69705, 12/01/2006).

Functional profiling measures the response of the whole cell to drug or drug combination exposure, using a combination of a morphologic (structure) and one or more metabolic (cell metabolism) endpoints. It is measuring at the cell "population" level than at the "single cell" level. The morphologic endpoint information is gathered by examing the state of hundreds of individual fresh "live" cells. The metabolic endpoints measure the combined metabolism of all cells present in the culture.

What a functional profile assay analogous to what a gene expression assay does, would measure 100,000 genes before and after drug exposure. The sort of gene expression assays that are being done measures gene expression in the "resting" state, prior to drug exposure. Gene-based tests cannot discriminate differing levels of anti-tumor activity occurring among different therapy drugs. Nor can they identify situations in which it is advantageous to combine the targeted drugs with other types of cancer drugs.

Gene profiling tests, important in order to identify new therapeutic targets and thereby to develop useful drugs, are still years away from working successfully in predicting treatment response for "individual" patients. Perhaps this is because they are performed on dead, preserved cells that were never actually exposed to the drugs whose activity they are trying to assess. In other words, they cannot predict chemo response.

It will never be as effective as the cell "function" method (is the cell being killed regardless of the mechanism), which exists today and is not hampered by the problems associated with gene expression tests (does the cell express a particular target that the drug is supposed to be attacking). That is because the cell-based profiling measures the net effect of all processes within the cancer, acting with and against each other in real time, and it tests "living" cells actually exposed to drugs and drug combinations of interest.

There are many mechanisms/pathways to altered cellular (forest) function (hence all the different "trees" which correlate in different situations). The forest is looked at, and not the trees. Functional profiling measures what happens at the end (the effects on the forest), rather than the status of the individual trees. Cancer is a complex disease and needs to be attacked on many fronts. The best thing to do is to combine these different tests in ways which make the most sense.

Cancer therapy needs to be thought of "outside the box" with personalized treatments for individual patients, and will require a combination of novel diagnostics and therapeutics. If some drugs are working for some people (not average populations), then obviously there are others out there who would also benefit. Who are those that would benefit? All the more reason to test the tumor first.

Improving cancer patient diagnosis and treatment through a combination of sub-cellular (molecular) level and at the cellular (cell function/cell culture) level, will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.

[jaminkw]

Greg: I read your post this morning and have questions, but with daylight saving time I'm already late getting ready for my trip to Orlando. It's my first Avastin maintenance treatment (the treatment that has sent me on this academic search), and the KOA where my husband and I stay has a very iffy internet service. I'll email the questions when I can.

Judy in Key West

[gpawelski]

I wrote this some time ago, but it fits this thread.

The "forest and trees" analogy can explained the fact that conventional chemo treatments try to kill "all" cancerous cells (along with non-cancerous cells). The whole forest of cells. The new "targeted" drugs go after a "pathway" within or on cancerous cells. Hence the "trees" instead of the "forest."

With "functional" cell-based assays, the "forest" is looked at and not the "trees." There are many pathways to altered cellular (forest) function (hence all the different "trees" which correlate in different situations). The "functional" profiling technique of cell-death assays, measures what happens at the end (the effects on the forest), rather than the status of the individual trees. Cancer is a complex disease and needs to be attacked on many fronts.

Cancer therapy needs to be thought of "outside the box" with "personalized" treatments for "individual" patients, and requires a combination of novel diagnostics and therapeutics. If "some" drugs are working for "some" people (not average populations), then obviously there are others out there who would also benefit. Who are those that would benefit? All the more reason to test the tumor first.

A cell culture assay with "functional" profiling, using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive). Cell "function" analysis doesn't claim to have a perfect model, but all retrospective studies have documented that killing cells in the test tube does correlate with dead cancer cells in the patient.

"Funtional" profiling measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell (forest), resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected (trees), "functional" profiling is measuring them through the surrogate of measuring if the cell is alive or dead.

For example, the epidermal growth factor receptor (EGFR) is a protein on the surface of a cell. EGFR inhibiting drugs certainly do target specific genes, but even knowing what genes the drugs target doesn't tell you the whole story. Both Iressa and Tarceva target EGFR protein-tyrosine kinases. But all the EGFR mutation or amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack.

It doesn't tell you if Iressa is better or worse than Tarceva or other drugs which may target this. There are differences. The drugs have to get inside the cells in order to target anything. So, in different tumors, either Iressa or Tarceva might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.

In an example of this testing, researchers have tested how well a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast and colorectal cancers. The pre-test can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer. One-size-does-not-fit-all.

What I wrote about Avastin in the Adjuvant Setting:

http://lchelp.org/l_community/viewtopic ... highlight=

[jaminkw]

Greg: Lots of important information but my question is about your reference to "Medicare-approved assays are the DISC, MTT and ATP, known as Oncologic in Vitro Chemoresponse Assays. In 2006, Medicare officially recognized these cancer assays as a special test category in Federal Regulations (42 CFR 414.510((3), 71 FR 69705, 12/01/2006)." I've never heard of these tests. I'm not on medicare until Feb 09 but do you know where these tests are being done and under what circumstances?

Judy in Key West

[gpawelski]

Judy

Three cell-based (cell-death) assay labs that are Medicare-approved are:

http://weisenthalcancer.com/index.htm

http://www.rational-t.com/

http://www.precisiontherapeutics.com/

The first two are doing the "functional profiling" assays. Don't know whether the third one is doing it also. They do have the knowledge and capacities to utilize them, but it is a question of do they. I do not have information about the other dozen labs that do this.

Two Medicare contractors (NHIC Medicare Services and Highmark Medicare Services) established reimbursement coverage policies for these assays, the same way that the Oncotype DX assay is being covered. Medicare bills for all these tests from any Medicare patients, anywhere in the United States, are billed through NHIC and Highmark Medicare Services because the test is conducted by approved laboratories in the area the tests are being performed. As far as payments are concerned, it is just as good as having a NCD. Numerous private payors pay for the tests also.