A New Generation of “Smart” Drugs

Chemotherapy has its uses. It has been the main approach to fighting cancer for many decades. But the non-specific nature of attack and resulting toxicity of chemotherapy drugs leaves much to be desired.  It is a little bit like carpet bombing.  You may get most of the bad guys (unless they are hiding in deep and heavily fortified bunkers), but the collateral damage to innocent people all around can be horrendous. There is increasing interest in immunotherapy, “smart” drugs that target specific cancer pathways.  You have heard of Campath, Rituxan, Revlimid etc. Now read about perifosine, a new drug making its debut in an interesting clinical trial.

“Future Medicine”

This is a journal I read once in a while, to keep an eye on new therapy concepts that may be coming down the road for our patients. Here is a recent article that I found interesting, you can read it for free by clicking on the link. Very often the concepts are just that – concepts, a gleam in the eye of some research group, who knows when or if it will ever pan out in the real world. But this time around I lucked out. The concept is not only an intriguing one, it is already in clinical trials. And wait for the punch line please – it is already in clinical trials for relapsed, refractory CLL patients. I am willing to bet most of you have not heard of it – yet. But you will in time, if I am reading the tea leaves right.

“War on Cancer” – Why We Have Not Won It

Despite the immense sums of money spent on the effort, with the exception of a few specific cancers (testicular cancer, Hodgkin’s lymphoma and a few leukemias –not CLL ), we are not close to winning the “War on Cancer”. One of the problems can be mistaken understanding of what is driving the cancer. Until recently, it was thought that all cancers were caused by very rapid growth rates of malignant cells – in other words, cancerous cells having too many babies too quickly. Since proliferation is thought to be at the heart of the accumulation of cancer cells, drugs were developed to target the proliferation mechanisms. As it turns out, there are two parts to the equation: excessive rate of birth of new cancer cells, as well as a reluctance of old cancer cells from dying a graceful death when it is their turn to kick the bucket. Drugs that just targeted the proliferation pathways are inadequate for the job. We need to tackle both ends of the spectrum: birth of new cancer cells and death of old cancer cells. In the case of CLL, it is particularly important to get a good handle on the second part, the ability of old CLL cells to dodge death and keep on living long past their time.

Built-in Suicide Mechanisms

All normal and healthy cells have built in mechanisms for committing suicide when it is their turn to die. When the cell receives the signal to die (the signal can be initiated by its neighbors or even within itself), the cell initiates self-destruct in an orderly fashion. This orderly process of cell suicide is called “apoptosis”. CLL cells are particularly poor at apoptosis. Even though they proliferate only slowly, their avoidance of apoptosis means their numbers will increase – slowly but surely. Think of it as a country where new babies are born at just a tad over the normal rate, but none of the old folks ever die. The result is a population explosion – just as in the case of CLL.  If we can re-educate cancer cells on the need to die in a peaceful fashion, no fuss and no mess and very little toxicity, we would have made major strides in winning the war on cancer.

Skin of the Cancer Cell

Just as you and I have skin to keep our innards nicely contained and separated from the outside, cells too have ‘skin’. It is called the plasma membrane. Floating around on the surface of the plasma membrane are little islands of fat – called lipid rafts. Cells need a wide range of receivers and broadcasters capable of receiving and sending messages, a way of interacting with the rest of the cells in the neighborhood. Much of this signaling machinery rides around on the lipid rafts. So, here is the concept: is there someway we can increase the concentration of the death signal receivers on the lipid rafts so that the “DIE!!” signal comes through loud and clear, the cell can no longer ignore the orders to commit suicide? As things stand, CLL cells are very capable of turning a deaf ear to death signals and that is the major part of the problem with this particular leukemia.

A New Class of Drugs

Researchers have been working with a new class of antitumor drugs called alkyl-phospholipids. Edelfosine and perifosine are but two examples of this class of drugs. These and their analogs are able to cluster a death receptor called Fas/CD95 in lipid rafts. Some of you who are interested in dietary methods of controlling cancer may have heard of resveratrol, obtained from the skin of red grapes. Recent research has shown that resveratrol too is capable of clustering death signal receivers in lipid rafts of cells. Who knew.

Laboratory and clinical work in several cancers has shown that perifosine is also able to mess with another important signaling pathway. AKT signaling is an important mechanism for cancer cell survival. It seems to be particularly important in CLL cell survival too, and that makes perifosine an interesting drug candidate for our guys. AKT pathway is receiving increasing scrutiny as a potential target for the next generation of immunotherapy drugs. In the next little while I will publish my long delayed review of CAL-101, another important drug in CLL clinical trials that also interferes with AKT signaling.

Hearing Aids For Deaf Cancer Cells

Recruitment of large numbers of apoptosis inducing molecules into lipid rafts has been shown to increase the rate at which the cell commits orderly suicide. Researchers love acronyms. A new one has been coined. CASMER stands for “cluster of apoptotic signaling molecule enriched rafts”. Phew. What a mouth full. But I think the concept itself is pretty nifty and not all that hard to understand. If you want a down-to-earth analogy, think of it as giving cancer cells a high tech hearing aid so that they can no longer turn a deaf ear to suicide orders from the rest of the body. CASMER causes death receptors and downstream signaling molecules inside the cell to come together effectively, so the job of suicide can proceed to its natural conclusion. Here is a link to the company (Keryx Biopharmaceuticals) website that lists the number and type of clinical trials that have been conducted with perifosine (KRX-04-01) in this country and Europe.

Cholesterol

Cholesterol is a critical constituent of lipid rafts and removing cholesterol from cell membrane disrupts CASMERs. Cancer cells are thought to be enriched in cholesterol, they have more cholesterol in their lipid rafts than normal healthy cells. Because of this, CASMERS may be the Achilles’ heel for cancer cells. Since CASMER mediated direct activation of apoptosis is likely to be independent of tumor suppressor genes such as p53, there is hope that this approach to treating cancer will not be hampered in patients that are p53 deleted. Now, pause a moment and think about that last sentence. I have written dozens of articles on this website as well as CLL Topics about the poor prognosis of patients with this particular FISH abnormality. Many of the standard issue drugs such as fludarabine will not work in p53 deleted patients. New drugs based on CASMER technology may be able to change that paradigm, since they can hopefully cause CLL cells to kill themselves, independent of whether or not they have working p53. Below is an abstract that describes some of this science.

Br J Pharmacol. 2010 May;160(2):355-66.

Disruption of cellular cholesterol transport and homeostasis as a novel mechanism of action of membrane-targeted alkylphospholipid analogues.

Carrasco MP, Jiménez-López JM, Ríos-Marco P, Segovia JL, Marco C.

Department of Biochemistry and Molecular Biology I, University of Granada, Spain. mpazcj@ugr.es <mpazcj@ugr.es>

Abstract

BACKGROUND AND PURPOSE: Alkylphospholipid (APL) analogues constitute a new class of synthetic anti-tumour agents that act directly on cell membranes. We have previously demonstrated that hexadecylphosphocholine (HePC) alters intracellular cholesterol traffic and metabolism in HepG2 cells. We now extended our studies to analyse the effects of other clinically relevant APLs, such as edelfosine, erucylphosphocholine and perifosine on intracellular cholesterol homeostasis. EXPERIMENTAL APPROACH: Using radiolabelled substrates we determined the effect of APLs on cholesterol metabolism and cholesterol traffic from the plasma membrane to the endoplasmic reticulum (ER). Protein levels and gene expression of the main proteins involved in cholesterol homeostasis were analysed by Western blot and RT-PCR respectively. Membrane raft and non-raft fractions were isolated from HepG2 cells by a detergent-free method. KEY RESULTS: All APLs inhibited the transport of cholesterol from the plasma membrane to the ER, which induced a significant cholesterogenic response in HepG2 cells. This response involved an increased gene expression and higher levels of several proteins related to the biosynthesis and the receptor-mediated uptake of cholesterol. Cell exposure to the APL-representative HePC enhanced the content of cholesterol mainly in the membrane raft fractions, compared with the untreated cells. CONCLUSIONS AND IMPLICATIONS: Membrane-targeted APLs exhibited a novel and common mechanism of action, through disruption of cholesterol homeostasis, which in turn affected specific lipid microdomains of cellular membranes.

PMID: 20423345

Perifosine Clinical Trial for CLL

Here is the link to clinicaltrials.gov that gives the full details of this trial being conducted at Duke University. If you are a relapsed and refractory CLL patient, volunteering to participate in this trial may be worth considering.  Contact information, inclusion criteria etc are given in the link above, please read it carefully.  Perifosine is an oral drug with reasonably well understood risk profile, based on its use in earlier clinical trials for multiple myeloma. There is very little hematological toxicity– such as destruction of platelets, neutrophils etc. Prior clinical trials in myeloma and Waldenstrom’s macroglobulinemia indicated patients may have significant GI tract issues such as nausea, vomiting and diarrhea. But the CLL clinical trial shows little of that in the patients recruited thus far (13 of them). This may be due to the fact that the dosing is different (twice daily, lower doses). Hey, whatever the reason, I will take the good news any time I can get it. Who wants to spend major portion of the day in the loo.

This is a Phase-II trial, looking to recruit 33 patients (13 spots have been filed already). As I said above, this is an oral drug, given twice daily for six months. Response rate will be measured within 3 months post treatment, but patients will be followed for 2 years to see what we can learn about overall survival and remission duration. My contact at Duke tells me there is also the option of continuing on the drug for more than 6 months if the physician and the patient feel this would be of help.

While this drug has been tested in other cancers including blood cancers, this is the first of its kind clinical trial in CLL patients. In the laboratory, CLL cells from patients have been shown to die very nicely when exposed to perifosine. Will it work as well in real live patients? The point of doing the clinical trial is to find the answer to that important question. Everything I have read thus far suggests toxicity side of the equation is likely to be low, therefore any rewards our guys get from this new drug class is all the more to be treasured. I have no doubt that down the road there will be combination therapies, combining perifosine and its analog drugs with more conventional drugs so as to get the cancer cells in the cross fire from multiple angles.

Recently I have been in contact with Dr. Daphne Friedman, a physician at Duke University who has a special interest in CLL. She is also the principle investigator for the perifosine clinical trial for CLL patients. She pointed me to their website dedicated to CLL and it has a lot more information on their perifosine clinical trial.

My Two Cents

There are a large number of ‘me-too’ clinical trials out there, tweaking the dosage a little, adding yet another drug to the alphabet soup of drug combos, substituting ofatumumab for Rituxan, digging out 40 year old drugs such as bendamustine and giving it a sexy new name like Treanda, anything to increase the ‘buzz’. An entirely new class of drugs, whose members are likely to have low toxicity and may work independent of p53 deletion, now that is worth sitting up and taking notice.

The US Food and Drug Administration (FDA) has just approved Fast Track designation for perifosine in the treatment of refractory advanced colorectal cancer.  Perifosine previously was granted fast Track and orphan drug status by the FDA for the treatment of relapsed/refractory multiple myeloma and is currently in phase-3  trials under special protocol assessment. I like it when a drug has potential use in a number of different diseases.  That way there is more chance that it will be developed, there will be money for continued research and its manufacture down the road if things pan out.  I think all of us know money makes the world go round. If drug companies had just CLL patients to depend on for their future revenues they would not be all that enthusiastic about developing it.  But solid cancers such as colorectal cancer are big mamas, with many more times the number of patients suffering  and dying from them.  If our guys can ride on the coat-tails of drug research done looking at more lucrative cancers, who am I to complain?  I will take the crumbs falling off of the table where the big boys are feasting, if that is the way to get research done in our small niche of the cancer world.

Clinical trials are the life blood of medical research. And there is no way of conducting clinical trials without patient recruitment. How sad would it be if perifosine and its sister drugs go on to make headlines as novel therapy options for other cancers (multiple myeloma comes to mind) but their use in CLL lags behind because of poor patient recruitment. I wish I had a dollar for each time CLL patients wrote wistful emails to me asking when we are likely to get our version of “magic” drugs similar to Gleevec.  Here is your chance to making that happen someday.

Each and every patient who participates in clinical trials is a true hero, a pioneer that shows the way to generations of patients to come after him/her.  But I think you know by now, I am a big fan of truly informed consent. So, please make the effort to inform yourself and if this clinical trial fits your needs I hope you will volunteer to participate in it. I am particularly intrigued by the possibility that this new drug may work in high risk patients with poor FISH profiles.  I have not met her, but Dr. Friedman sounds very nice and she has agreed to answer any questions you may have about their clinical trial.  So, post your questions in the discussion section below and I will make sure she gets to see them.  It may take a day or two for me to post her responses here.