Kinase Inhibitors Could Keep Cancer Patients Alive Much Longer

High doses of kinase inhibitors

According to laboratory oncologist Dr. Larry M. Weisenthal, high dose pulse Kinase inhibitors can be effective for central nervous system (CNS) disease, so long as resistance has not developed.

Laboratories like Rational Therapeutics and Weisenthal Cancer Group have been testing erlotinib (Tarceva), lapatinib (Tykerb), sorafenib (Nexavar) and vemurafenib (Zelboraf) - the 'nib' drugs, along with about eight other kinase inhibitors, in actual human tumor primary culture micro-spheroids (microclusters), in various cancers.

This is exactly the area they are interested in. Specifically re-examine the role of all of these compounds in a wide variety of disease. They have often recommend higher dose, pulse/intermittent therapy, in combination with other agents. In addition, they have been successfully increasing the dose of erlotinib (Tarceva) to recapture patients.

These drugs are not identical, however. Some work in some tumors, while others do not -- yet in other tumors, the drugs which didn't work do work and vice versa. You'd think that if they all had the identical mechanism of action that they'd all work or they'd all not work; but that's not the way it goes.

It may have something to do with entry into the cell; efflux out of the cells; inactivation, or whatever. It does show that there's much more to the action of a drug than simply the presence of a "target" molecule.

This is an important development. I've had a number of inquiries on cancerfocus.org about the high-dose (or pulse-dosing) of the 'nib' drugs. This article is quite excellent in describing it (and the other kinase drugs). I'm hoping to get some real good reports from the AACR Annual Meeting from April 6-10 in Washington, D.C. Professor Paul Workman is a very hot ticket and is scheduled for a number of venues at the meeting. Dr. Robert Nagourney has a poster presentation on the comparison of erlotinib (Tarceva), lapatinib (Tykerb) and afatinib (planned trade name Tomtovok), previously BIBW 2992.

The success of the original kinase inhibitors had raised hope that drugs that target key kinases underlying other cancers, such as members of the human epidermal growth factor receptor (HER) family, might be similarly efficacious. However, several small-molecule inhibitors of HER family kinases have shown limited efficacy in HER2-driven breast cancers, despite effective inhibition of kinase activity. An article in Nature, 7 Jan 2007, scientists had provided an explanation for this phenomenon: failure to completely inhibit the kinase activity of HER2 allows oncogenic signaling through the kinase-inactive family member HER3 to continue.

Signaling in the HER family, which consists of epidermal growth factor receptor (EGFR), HER2, HER3 and HER4, involves receptor dimerization and transphosphorylation, which leads to the activation of various pathways, including the potentially oncogenic phosphatidyl-inositol 3-kinase (PI3K)/Akt pathway. While these agents are effective at inhibiting EGFR and HER2 phosphorylation in patients' tissues and tumors, Akt activity is not inhibited as might be anticipated in many patients, which could explain the limited clinical activity of the drugs.

Patients with HER2-positive breast cancer being treated with anti-HER2 therapy may be able to prevent or delay resistance to the therapy with the addition of a PI3K kinase inhibitor to their treatment regimens. Dual simultaneous inhibition of both HER2 and PI3K may prolong the use of anti-HER2 therapies in women with breast cancer. Designing 'targeted' anticancer drugs begins with identifying the genes or proteins that are specific to the development of cancer and testing whether blocking those genes or proteins gets rid of the cancer. Genetic (molecular) tests are instrumental in accomplishing this task. 

However, understanding 'targeted' treatments begins with understanding the cancer cell. Every tissue and organ in the body is made of cells. In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific 'pathways' that involve various genes and proteins in a cell. 

Genetic-based testing examines a single process within the cell or a relatively small number of process. The aim is to tell if there is a theoretical predispostion to drug response. Phenotype analysis not only examines for the presence of genes and proteins but also for their 'functionality' (their interaction with other genes, proteins, and processes occurring within the cell, and for their response to 'targeted' drugs). 

Genetic-based testing involves the use of dead, formaldehyde preserved cells that are never exposed to 'targeted' drugs. Genetic-based tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell. 

Genetic-based tests cannot discriminate among the activities of different drugs within the same class. Instead, it assumes that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Genetic-based tests tell us anything about drug combinations. 

Phenotype analysis (functional profiling) looks at 'fresh' living cancer cells. It assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. It can discriminate differing anti-tumor effects of different drugs within the same class. It can also identify synergies in drug combinations. 

When considering a 'targeted' cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect. Although presence of a 'targeted' defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug. 

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy. Sometimes a drug will inhibit the 'target' but not stop the growth of cancer. Not all genes and proteins have a critical role in the survival and growth of cancer cells. 

The are many pathways to altered cellular (forest) function, hence all the different 'trees' which correlate in different situations. Improvement can be made by measuring what happens at the end of all processes (the effects on the forest), rather than the status of the individual trees (pathways/mechanisms). You still need to measure the net effect of all processes, not just the individual molecular (gene/protein) targets.

You can see why laboratory oncologists like Drs. Nagourney and Weisenthal have been interested in this. Nagourney will be presenting some information about the comparisons of various kinases.

Heat-shock factor reveals its unique role in supporting highly malignant cancers

Whitehead Institute researchers have found that increased expression of a specific set of genes is strongly associated with metastasis and death in patients with breast, colon, and lung cancers. Not only could this finding help scientists identify a gene profile predictive of patient outcomes and response to treatment, it could also guide the development of therapeutics to target multiple cancer types.



The genes identified are activated by a transcription factor called heat-shock factor 1 (HSF1) as part of a transcriptional program distinct from HSF1's well-known role in mediating the response of normal cells to elevated temperature. In normal cells, a variety of stressors, including heat, hypoxia, and toxins, activate HSF1 leading to increased expression of so-called heat-shock or chaperone proteins that work to maintain protein homeostasis in stressed cells.



Scientists have known for some time that many cancer cells have higher levels of chaperones and that elevation of these proteins is important for survival and proliferation of tumor cells. Now, however, researchers in the lab of Whitehead Member Susan Lindquist report that HSF1 supports cancers not only by increasing chaperones, but by unexpectedly regulating a broad range of cellular functions that are important for the malignant behavior of tumor cells.



This activity allows for the development of the most aggressive forms of three of the most prevalent cancers, breast, lung, and colon. The findings, published this week in the journal Cell, build on earlier research from the Lindquist lab showing that elevated levels of HSF1 are associated with poorer prognosis in some forms of breast cancer. "This work shows that HSF1 is fundamentally important across a broad range of human cancers, cancers of various types from all over the body turn on this response," says Sandro Santagata, a postdoctoral researcher in the Lindquist lab. "That's very interesting. It suggests how important HSF1 must be for helping tumors become their very worst."



In addition to confirming that this gene activation program differs from that associated with heat shock, the researchers found that in many tumors, it becomes active in virtually all of the tumor's cells. "This demonstrates it isn't simply regions of microenvironmental stress within a tumor that drive HSF1 activity, but rather that HSF1 activation is wired into the core circuitry of cancer cells, orchestrating a distinct gene regulatory program that enables particularly aggressive phenotypes," says Marc Mendillo, a postdoctoral researcher in the Lindquist lab. "This suggests HSF1 itself could be a great therapeutic target."



Luke Whitesell, an oncologist and senior research scientist in the Lindquist lab, concurs that HSF1 is a conceptually appealing target for therapeutic intervention, noting that suppressing HSF1 for short periods of time should have minimal consequences on normal cells.

However, he adds, actually developing such a drug could be problematic. "Coming up with a drug that disrupts HSF1's interaction with DNA, which is how it activates all of these genes, that is going to be really tough," says Whitesell. "No one has come up with a clinically useful drug that directly interrupts a transcription factor's interaction with DNA yet. But there are ways to disrupt a transcription factor's function indirectly, as opposed to directly targeting the protein itself. What we have now from this research is a new view of the landscape and the possibilities for drug discovery and development that are out there."