Is There a Role for PI3k Inhibitors in Breast Cancer? Maybe.

Over the past decades oncologists have learned that cancer is driven by circuits known as signal transduction pathways. Signal_transduction_pathways.svgThe first breakthroughs were in chronic myelogenous leukemia (CML) where a short circuit in the gene as c-Abl caused the overgrowth of malignant blasts. The development of Imatinib (Gleevec) a c-Abl inhibitor yielded brilliant responses and durable remissions with a pill a day.

The next breakthrough came with the epidermal growth factor pathway and the development of Gefitinib (Iressa) and shortly thereafter Erlotinib (Tarceva). Good responses in lung cancers, many durable were observed and the field of targeted therapy seemed to be upon us.

220px-PI3kinaseAmong the other signal pathways that captured the imagination of the pharmaceutical industry as a potential target was phospho-inositol-kinase (PI3K). Following experimental work by Lew Cantley, PhD, who first described this pathway in 1992, more than a dozen small molecules were developed to inhibit this cell signal system.

The PI3K pathway is important for cell survival and regulates metabolic activities like glucose uptake and protein synthesis. It is associated with insulin signaling and many bio-energetic phenomena. The earliest inhibitors functioned downstream at a protein known as mTOR, and two have been approved for breast, neuroendocrine and kidney cancers. Based on these early successes, PI3K, which functions upstream and seemed to have much broader appeal, became a favored target for developmental clinical trials.

The San Antonio Breast Cancer Symposium is one of the most important forums for breast cancer research. The December 2014 meeting featured a study that combined one of the most potent PI3K inhibitors, known as Pictilisib, with a standard anti-estrogen drug, Fulvestrant, in women with recurrent breast cancer. The FERGI Trial only included ER positive patients who had failed prior treatment with an aromatase inhibitor (Aromasin, Arimidex or Femara). The patients were randomized to receive the ER blocker Fulvestrant with or without Pictilisib.

With seventeen months of follow-up there was some improvement in time to progressive disease, but this was not large enough to achieve significance and the benefit remains unproven. A subset analysis did find that for patients who were both ER (+) and PR (+) a significant improvement did occur. The ER & PR (+) patients benefitted for 7.4 months on the combination while those on single agent Fulvestrant for only for 3.7 months.

The FERGI trial is more interesting for what it did not show. And that is that patients who carried the PI3K mutation, the target of Pictilisib, did not do better than those without mutation (known as wild type). To the dismay of those who tout the use of genomic biomarkers like PI3K mutation for patient drug selection, the stunning failure to identify responders at a genetic level should send a chill down the spine of every investor who has lavished money upon the current generation of genetic testing companies.

It should also raise concerns for the new federal programs that have designated hundreds of millions of dollars on the new “Personalized Cancer Therapy Initiatives” based entirely on genomic analyses. The contemporary concept of personalized cancer care is explicitly predicated upon the belief that genomic patient selection will improve response rates, reduce costs and limit exposure to toxic drugs in patients unlikely to respond.

This unanticipated failure is only the most recent reminder that genomic analyses can only suggest the likelihood of response and are not determinants of clinical outcome even in the most enriched and carefully selected individuals. It is evident from these findings that PI3K mutation alone doesn’t define the many bioenergetic pathways associated with the phenotype. This strongly supports phenotypic analyses like EVA-PCD as better predictors of response to agents of this type, as we have shown in preclinical and clinical analyses.

Investigators in Boston Re-Invent the Wheel

A report published in Cell from Dana-Farber Cancer Institute describes a technique to measure drug cov150hinduced cell death in cell lines and human cancer cells. The method “Dynamic BH3 profiling” uses an oligopeptidic BIM to gauge the degree to which cancer cells are “primed” to die following exposure to drugs and signal transduction inhibitors. The results are provocative and suggest that in cell lines and some human primary tissues, the method may select for sensitivity and resistance.

We applaud these investigators’ recognition of the importance of phenotypic measures in drug discovery and drug selection and agree with the points that they raise regarding the superiority of functional platforms over static (omic) measures performed on paraffin fixed tissues. It is heartening that scientists from so august an institution as Dana-Farber should come to the same understanding of human cancer biology that many dedicated researchers had pioneered over the preceding five decades.

Several points bear consideration. The first, as these investigators so correctly point out: “DBP should only be predictive if the mitochondrial apoptosis pathway is being engaged.” This underscores the limitation of this methodology in that it only measures one form of programmed cell death – apoptosis. It well known that apoptosis is but one of many pathways of programmed cell death, which include necroptosis, autophagy and others.

While leukemias are highly apoptosis driven, the same cannot so easily be said of many solid tumors like colon, pancreas and lung. That is, apoptosis may be a great predictor of response except when it is not. The limited results with ovarian cancers (also apoptosis driven) are far from definitive and may better reflect unique features of epithelial ovarian cancers among solid tumors than the broad generalizability of the technique.

A second point is that these “single cell suspensions” do not recreate the microenvironment of human tumors replete with stroma, vasculature, effector immune cells and cytokines. As Rakesh Jain, a member of the same faculty, and others have so eloquently shown, cancer is not a cell but a system. Gauging the system by only one component may grossly underestimate the systems’ complexity, bringing to mind the allegory of elephant and the blind man. Continuing this line of reasoning, how might these investigators apply their technique to newer classes of drugs that influence vasculature, fibroblasts or stroma as their principal modes of action? It is now recognized that micro environmental factors may contribute greatly to cell survival in many solid tumors. Assay systems must be capable of capturing human tumors in their “native state” to accurately measure these complex contributions.

Thirdly, the ROC analyses consistently show that this 16-hour endpoint highly correlates with 72- and 96-hour measures of cell death. The authors state, “that there is a significant correlation between ∆% priming and ∆% cell death” and return to this finding repeatedly. Given that existing short term (72 – 96 hour) assays that measure global drug induced cell death (apoptotic and non-apoptotic) in human tumor primary cultures have already established high degrees of predictive validity with an ROC of 0.89, a 2.04 fold higher objective response rate (p =0.0015) and a 1.44 fold higher one-year survival (p = 0.02) are we to assume that the key contribution of this technique is 56 hour time advantage? If so, is this of any clinical relevance? The report further notes that 7/24 (29%) of ovarian cancer and 5/30 (16%) CML samples could not be evaluated, rendering the efficiency of this platform demonstrably lower than that of many existing techniques that provide actionable results in over 90% of samples.

Most concerning however, is the authors’ lack of recognition of the seminal influence of previous investigators in this arena. One is left with the impression that this entire field of investigation began in 2008. It may be instructive for these researchers to read the first paper of this type in the literature published in in the JNCI in 1954 by Black and Spear. They might also benefit by examining the contributions of dedicated scientists like Larry Weisenthal, Andrew Bosanquet and Ian Cree, all of whom published similar studies with similar predictive validities many years earlier.

If this paper serves to finally alert the academic community of the importance of human tumor primary culture analyses for drug discovery and individual patient drug selection then it will have served an important purpose for a field that has been grossly underappreciated and underutilized for decades. Mankind’s earliest use of the wheel dates to Mesopotamia in 3500 BC. No one today would argue with the utility of this tool. Claiming to have invented it anew however is something quite different.

Bevacizumab In Colon Cancer – “A Shot Across The Bowel”

Colon2 130320.01 lo resAn E-Publication article in the February Journal of Clinical Oncology analyzes the cost efficacy of Bevacizumab for colon cancer. Bevacizumab, sold commercially as Avastin, has become a standard in the treatment of patients with advanced colorectal cancer. Indeed, Bevacizumab plus FOLFOX or FOLFIRI, are supported by NCCN guidelines and patients who receive one of these regimens are usually switched to the other at progression.

A Markov computer model explored the cost and efficacy of Bevacizumab in the first and second line setting using a well-established metric known as a Quality-Adjusted Life Year (QALY). In today’s dollars $100,000 per QALY is considered a threshold for utility of any treatment. To put this bluntly, the medical system values a year of yavastinour life at $100,000. The authors confirmed that Bevacizumab prolongs survival but that it does so at significantly increased costs. By their most optimistic projections, Bevacizumab + FOLFOX come in at more than $200,000 per QALY. Similar results were reported for Canadian, British and Japanese costs. Though more favorable, the results with FOLFIRI + Bevacizumab still came in above the $100,000 threshold.

No one doubts that Bevacizumab provides improved outcomes. It’s the incremental costs that remain an issue. Society is now confronting an era where the majority of new cancer agents come in at a cost in excess of $10,000 per month. Where and how will we draw the line that designates some treatments unaffordable? On the one hand, clinical therapies could be made available only to the “highest bidder.” However, this is contrary to the western societal ethic that holds that medical care should be available to all regardless of ability to pay. Alternatively, increasingly narrow definitions could be applied to new drugs making these treatments available to a shrinking minority of those who might actually benefit; a form of “evidence-based” rationing. A much more appealing option would be to apply validated drug predication assays for the intelligent selection of treatment candidates.
Avastin-MOA-Overview
In support of the latter, the authors state, “Bevacizumab potentially could be improved with the use of an effective biomarker to select patients most likely to benefit.” This is something that genomic (DNA) profiling has long sought to achieve but, so far, has been unable to do. This conceptual approach however is demonstrably more attractive in that all patients have equal access, futile care is avoided and the costs saved would immediately provide highly favorable QALY’s as the percentage of responders improved.

Similar to the recent reports from the National Health Service of England, the American public now confronts the challenge of meeting the needs of a growing population of cancer patients at ever-higher costs. It is only a matter of time before these same metrics described for colon cancer are applied to lung, ovarian and other cancers for which Avastin is currently approved.

At what point will the American medical system recognize the need for validated predictive platforms, like EVA-PCD analyses, that have the proven capacity to save both money and lives? We can only wonder.

Cancer Patients Need Answers Now!

I read a sad editorial in the Los Angeles Times written by Laurie Becklund, former LA Times journalist. It is, in essence, a self-written obituary as the patient describes her saga beginning almost 19 years earlier, when she detected a lump in her breast. With stage I breast cancer she underwent standard therapy and remained well for 13 years until recurrence was heralded by disease in bone, liver, lung and brain. Given a dire prognosis she became a self-made expert, conducting research, attending conferences, and joining on-line forums under the name “Won’t Die of Ignorance.” Despite her heroic effort Ms. Becklund succumbed to her illness on February 8. She was 66.

Ms. Becklunla-laurie-becklund-cropp-jpg-20150209d experienced the anguish that every patient feels when his or her own individual and highly personal needs simply aren’t being addressed. She opines that entities like the Susan G. Komen Fund, which has raised over $2.5 billion in the last 20 years, “channels only a fraction of those funds into research or assistance to help those who are already seriously sick.” She continues, “We need people, patients, doctors, scientists, politicians, industry and families to make a fresh start.” Her frustration is palpable as she states her outcome seemed to be based on the roll of the dice, like playing “Chutes and Ladders.”

The author’s plight is shared by the millions of patients who are confronting advanced cancers. They are not interested in “why” or “how” their cancers came to be. They can no longer benefit from early detection or cancer awareness campaigns. They need practical, actionable, clinical answers today.

Ms. Becklund’s commentary resonates with me and with everyone who has cOutliving Cancerancer or knows someone who does. As an oncology fellow at Georgetown, I found myself losing patient after patient to toxic and largely ineffective treatments, all despite my best efforts. I described this in my book “Outliving Cancer.” It was then that I decided that I would dedicate myself to meeting the individual needs of each of my patients and I have used a laboratory platform (EVA-PCD) to do so. I have encountered surprising resistance from clinicians and researchers who seem to prefer the glacial pace of incremental advancement found in population studies over individual solutions found in the study of each patient’s unique biology. Ms. Becklund correctly points out that every treatment must meet each individual’s need.

The role of the scientist is to answer a question (treatment A vs. treatment B) while that of the clinical physician must be to save a life. Every patient is an experiment in real time. It may well be that no two cancer patients are the same. Indeed, the complexity of carcinogenesis makes it very possible that every patient’s cancer is an entirely new disease, never before encountered. Although cancers may look alike, they may be biologically quite distinct. Meaningful advances in cancer will only occur when we learn to apply all available technologies to treat patients as the individuals that they are. Let us hope that Ms. Becklund’ s final essay does not fall upon deaf ears.

In Cancer Research: An Awakening?

In 2005, as the Iraq War reached a low point with casualties mounting and public support dwindling, Sunni tribesman in the Anbar Province arose to confront the enemy. Joining together as an ad hoc army these fighters turned the tide of the war and achieved victories in the face of what had appeared at the time, to be overwhelming odds.

I am reminded of this by an article in The Wall Street Journal by Peter Huber and Paul Howard of the Manhattan Institute that examined the bureaucracy of drug development. It raised the question: Are new cancer treatments failures or is the process by which they are approved a failure? They describe “exceptional responders” defined as patients who show unexpected benefits from drug treatments. Using molecular profiles, they opine, scientists will unravel the mysteries of these individuals and usher in an era of personalized medicine. Thus, rigid protocols that use drugs based upon tumor type e.g. lung vs. colon fail because they do not incorporate the features that make each patient unique – an awakening.

The example cited is from Memorial Sloan-Kettering where a patient with bladder cancer had an unexpected response to the drug Everolimus (approved for kidney cancer). Subsequent deep sequencing identified a genetic signature associated with sensitivity to this drug. While it is a nice story, I already knew it very well because it had been repeated many times before and would in the past have been dismissed as an “anecdote.” It is precisely because of its rarity that it has been repeated so many times.

The WSJ analysis strikes a familiar chord. For decades, we have decried the failure of rigid clinical trials that underestimate a patient’s unique biology yet cost millions, even billions of dollars, while denying worthy candidates new treatments under stultifying disease-specific designs.

Well Tray Closeup2 smallWe pioneered phenotypic (functional) analyses (the EVA-PCD platform) to examine whole cell models as we explored drug response profiles, novel combinations and new targets. It is regrettable that these WSJ authors, having raised such important issues, then stumble into the same tantalizing trap of molecular diagnostics, and call for bigger, better, faster genomic analyses.

Cancer patients need to receive treatments that work. They do not particularly care why or how they work, just that they work. These authors seem to perpetuate the myth that we must first understand why a patient responds before we can treat them. Nothing could be further from the truth.

Alexander Fleming knew little about bacterial cell wall physiology when he discovered penicillin in 1928, and William Withering knew nothing about the role of muscle enzymes in congestive heart failure when he discovered digoxin extracts in 1785. Would anyone argue that we should have waited decades, even centuries to apply manifestly effective therapies to patients because we did not have the “genes sequenced?’

We may be witness to an awakening in cancer drug development. It may be that a new understanding of individualized patient response will someday provide better outcomes, but platforms with the proven capacity to connect patients to available treatments should be promoted and applied today.

In Cancer Care, It Appears that More Is Less

With the interest in “value oncology” and cost containment, a report appeared in the December 2014 Journal of Clinical Oncology that analyzed the impact of the Medicare Prescription Drug Act of 2003 (MMA) on chemotherapy administration in an environment of diminishing reimbursement to physicians.

Prior to the passage of the MMA, oncologists were compensated at 95% of the average wholesale price of a drug. The government accounting office found that the larger medical oncology practices could form “buyers groups” and purchase drugs at lower prices allowing them to pocket the difference. A 2003 New York Times article decried the practice as a “Chemotherapy Concession” and Medicare responded. The MMA of 2003 changed the policy so that chemotherapy drugs were reimbursed at the national average sale price plus 6%. It was hoped that this would result in cost savings.

Practices were divided into Fee-For-Service and Integrated-Health-Networks, the latter largely HMOs and the Veterans’ Administration. It was expected that integrated networks would be less affected since their physicians are salaried and an 11% disparity between the two groups was noted for MMA agents. However, a number of interesting, unexpected and instructive trends emerged.

First, contrary to expectations, the overall use of chemotherapy actually increased following the passage of the MMA.

Second, the cost of cancer care continued to increase unabated following the passage of the MMA.

Finally, changes in drug use appeared to be disease-specific. Colorectal and small cell lung cancer patients saw a decline in the use of MMA affected drugs while non-small lung cancer showed an increase for both fee-for-service and integrated networks. With the overall use of MMA drugs in lung cancer increasing by 1.6 fold, the same drug use increase in the integrated (salaried) groups was 6.3 fold higher.

Among the findings the authors note “reimbursement after MMA passage appears to have had less impact on prescribing patterns in fee for service than the introduction of new drugs and clinical evidence.” This gives the lie to the idea that practicing oncologists are driven by self-gain, a popular narrative in the current political environment.

The authors did find that passage of MMA “resulted in consolidations and acquisitions of practices by hospitals, many of which were able to purchase chemotherapy drugs at discounted rates through the federal 340B* program. Although the full impact of these changes is not known, the shift of chemotherapy from community practices to hospital outpatient settings is associated with higher total costs.”

Community fee-for-service oncologists represent a qualified, yet under-appreciated resource for patients. While their academic brethren bask in the limelight, it is private practitioners who must make sense of the complex and overly dose-intensive treatment schedules handed down to them by ivory tower investigators. We now come to learn that while fee-for-service doctors have been forced to consolidate, join hospital systems, or retire, the cost of cancer care has actually climbed by 66% since the passage of MMA.

It would appear that this experiment has failed. Costs were not contained and drug use was not curtailed. What other bright ideas can we expect from policymakers who seem intent on bending medical care to their wishes at the expense of doctors and their patients?

 

*The 340 B program was originally created by the Federal government to allow charitable hospitals to save money on expensive drugs by allowing them to purchase them at deep discounts. Over time a growing number of “not-for-profit” hospitals demanded the same consideration. Subsequent analyses have found that the majority of the hospitals that now take advantage of 340B actually provide less charity care than the national average. Hospitals that charge full fee for drug administration can then pocket the difference.

Rationed or Rational: The Future of Cancer Medicine

Disturbing news from Britain’s Health Service on Monday, January 12, described the National Health Services’ decision to “delist” 25 of the nation’s 84 currently available chemotherapy drugs from their formulary. Citing the rising cost of cancer therapy Professor Peter Clark, chair of the Cancer Drug Fund said that the CDF, originally established in 2011, had already exceeded its annual budget. From ₤280 million in 2014 the costs for 2015 are projected to rise to ₤340 million. In defense of the policy Dr. Clark said the delisted drugs “did not offer sufficient clinical benefit.”

avastinAn examination of the delisted drug should raise concern for medical oncologists. Among those delisted are Bevacizumab (Avastin) for colorectal cancer, Eribulin (Haloven) and Lapatinib (Tykerb) for breast cancer and Pemetrexed (Alimta) for advanced lung cancer. Additionalhalaven deletions include Bendamustine (Treanda) for some non-Hodgkin’s lymphoma, Bortezomib (Velcade) for relapsed mantle cell lymphoma and Waldenström’s macroglobulinemia. Bortezomib will also be limitedvelcade_MP_thumb in some cases of myeloma, while Cetuximab will be unavailable as second or third line treatment in colorectal cancer. For American oncologists these agents have become standards of care.

Many physicians in England are outraged. Mark Flannagan, executive chief of the Beating Bowel Cancer Fund described this as “bad news for bowel cancer patients” suggesting that 65% of patients with advanced colorectal cancers will confront the risk of an earlier death. Despite these draconian measures physicians may still have the opportunity to request delisted drugs under what is described as “exceptional cases.”

The breadth and scope of the drug restrictions are surprising. After all, Pemetrexed is one of the most widely used treatments for advanced lung cancer, Bevacizumab has become an established part of colorectal cancer management and Eribulin is a favored salvage regimen in recurrent breast. The withdrawal of Bortezomib, an active agent in mantle cell, Waldenström’s and myeloma, will not be suffered lightly by patients in need.

Are the problems confronting the UK an early harbinger of the same for the American medical system?

With aging populations in western societies and increasingly sophisticated medical technologies, the cost of medical care, particularly cancer care may soon become unmanageable. UK’s centralized medical care delivery through the National Health Service, a single payer system, was designed to save money. Despite its high-minded intentions, the NHS appears to be failing. While spending more money each year the dissatisfaction with medical delivery only grows. A nearly 12% increase in health care per person expenditures in England between 2009 and 2013 (₤1712 to ₤1912) was met with an 18% increase in patient complaints.

Among the problems are progressive layers of middle management that add cost without providing care.  Physicians find it more difficult to do their jobs while people inexpert in the delivery of medical care have been given decision-making power. As the English population has come to look upon health care as a right, some overuse medical services, even ER’s, for non-serious conditions. Reformers have suggested the solution may lie in charging fees for appointments or requiring an annual membership fee. In today’s political milieu however, few elected officials are likely to relish policies that end “free health care” in England.

What might solve this dilemma for medical oncology? An obvious solution is to apply resources where they are most likely to benefit patients, e.g. personalized care. While this seemed a pipe dream 20 years ago when we first introduced the concept, a growing chorus of scientists now embraces the idea. With their focus almost exclusively on genomics this new cadre of clinical investigators describe a future where each patient gets exactly the right treatment.

We applaud this thinking and fully agree. However, we must be prepared to use all platforms to achieve this worthy goal. To fill the current void phenotypic analyses offer substantive benefits. By capturing cancer biology at a functional level, these studies identify true “driver mutations,” and have the capacity to examine synergy and sequence-dependence, both beyond the scope of genomic analyses.

As human tumor primary culture analyses (such as EVA-PCD) have already been shown to double objective response rates and improve one-year survival, it is time for government officials and policymakers to re-examine the benefits of drug selection technologies that are available today.

Will the future of cancer medicine in the UK and the US be rationed under the duress of rising costs, or rational, through the application of available technologies capable of making intelligent cost- and life-saving decisions? That remains to be seen.

Breakthroughs In Cancer?

Coco Chanel, the icon of 20th century fashion once said, “Only those with no memory insist on their originality.” I am reminded of this quote as I review recent discoveries in cancer, among them, the recognition that cancer represents a dysregulation of cellular metabolism.

The field of metabolomics (the systematic study of cellular energy production), explored by investigators over the last decade is little more than the rediscovery of enzymology (a branch of biochemistry that deals with the properties, activity, and significance of enzymes), biochemistry (the science dealing with the chemistry of living matter) and stoichiometry (the part of chemistry that studies amounts of substances that are involved in reactions), pioneered by investigators like Albert Lehninger, Hans Krebs, Otto Warburg, and Albert Szent-Gyorgyi. These innovators used crude tools to explore the basis of human metabolism as they crafted an understanding of bioenergetics (the study of the transformation of energy in living organisms) and oxidative phosphorylation (processes occurring in the cell’s mitochondrion that produce energy through the synthesis of ATP (energy carrier of the body).

More recently, scientists wedded to genomics have slowly come to recognize the limitations of their approach and have returned to the field of phenotypic (the observable physical or biochemical characteristics of an organism analysis.

While newcomers to the field claim to be the first to recognize the role of cellular biology in tumor biology, a cadre of dedicated investigators had already charted these waters decades earlier. Beginning with the earliest studies by Siminovitch, McCulloch and Till, subsequent investigations by Sydney Salmon and Anne Hamburger, developed the earliest iteration of cellular studies for the examination of cancer biology in primary culture.

Ovarian Cancer

Ovarian Cancer

The work of Black and Spear, published in the 1950s similarly explored the study of human cellular behavior for the study of cancer research. While Larry Weisenthal, Andrew Bosanquet and others established useful predictive methodologies to study cellular phenotype, their seminal contributions have gone largely unrecognized.

Today, start-up companies are examining cellular biology to predict cancer outcomes, each claiming to be the first to recognize the importance of cell death events in primary culture. The most recent and widely touted in the literature is the use of mouse avatars. Implanting biopsied explants of tissue from patients into nude mice, they grow the cancers to desired size and then inject the drugs of interest to show tumor shrinkage. To the discerning eye however, it obvious that this represents little more than an expensive, inefficient, and extremely slow way to achieve that, which can be done more easily, inexpensively, and quickly in a tissue culture environment.

When I read the promotional material of some of the new entrants to this field, I am reminded of another quote, that of Marie Antoinette, who said, “There is nothing new except what has been forgotten.”

A New Use for One of the Oldest “New” Drugs

With the profusion of new targeted agents entering the clinical arena, a report from the American Society of Hematology bears consideration.

The trial known as the SORAML trial enrolled 276 patients with newly diagnosed acute myelogenous leukemia. The patients were between the ages of 18 and 60. All patients received a standard chemotherapy regimen. The patients were then randomized to receive Sorafenib or placebo. Patients on the Sorafenib arm then remained on a maintenance therapy for twelve months.

While the achievement of complete remission was almost identical between the two arms at 59% and 60%, the event free survival demonstrably favored the Sorafenib group at 20.5 months versus 9.2 months. At three years of follow-up 40% of the Sorafenib group were well with only 22% of the placebo group still in remission. This corresponds to a three-year relapse free survival of 38% for placebo and 56% for Sorafenib (P=0.017).

The results are of interest on several levels.
1.    Sorafenib a multitargeted tyrosine kinase inhibitor was approved in December 2005 for the treatment of renal cell carcinoma. This makes Sorafenib one of the first targeted agents to achieve FDA approval.

2.     Sorafenib has many modes of action and it is not entirely clear which of its functions were responsible for the superior survival in this AML study.

3.    Sorafenib’s approval reflects a rather convoluted and interesting history. When first developed the drug was designed to target the oncogene B-Raf. As a result the drug was introduced into early clinical trials for the treatment of advanced melanoma, a disease known to be associated with B-Raf mutation. As the drug proved ineffective, it appeared unlikely to gain FDA approval. That is, until it showed cross reactivity with VEGF pathway associated with tumor cell vascularity. A successful trial published in the New England Journal of Medicine then led to the approval.

Now, nine years later this old new drug has gained new life. This time in acute myelogenous leukemia.

The term “dirty drug” refers to agents that target many kinases at the same time. Sorafenib is an example of a “dirty drug.” However it is Sorafenib’s “dirty drug” quality that led first to its approval and most likely now leads to its application in AML. This reflects the fact that Sorafenib may be inhibiting B-Raf signaling associated with the common mutation in Ras upstream of B-Raf or it may reflect Flt3 a secondary activity associated with Sorafenib.

Indeed B-Raf and Flt3 may not be upregulated in every patient, but could serve a function of permissive activity granting an additional survival signal to the AML cells as they go through induction therapy. These subtleties of drug effect may escape genomic analysis as the true “target” may not be mutated, upregulated or amplified. No doubt the investigators in this study will conduct gene sequencing to determine whether there is a driver mutation associated with the advantage reported in this clinical study. What will be intriguing is to determine whether that advantage is an abnormal gene functioning within these cancerous cells or possibly a normal gene functioning abnormally in these cancer cells. More to come.

The Case for the Metabolic Basis of Cancer Gains Traction

Researchers from the Huntsman Cancer Institute at the University of Utah reported an interesting finding with far-reaching implications.

In their study of the rare tumor known as alveolar soft part sarcoma (ASPS), they examined the well-established chromosomal translocation that occurs between chromosomes 17 and X. This results in the 250px-Protein_ASPSCR1_PDB_2al3production of a fusion protein dubbed ASPSCR1-TFE3. Like other fusion proteins described in malignancies such as lymphoma, acute pro-myelocytic leukemia and chronic myelogenous leukemia, a novel function occurs when two disparate genomic elements are spliced together.

In this instance, the ASPSCR1-TFE3 gene product functions as a lactate transporter. Strikingly, every mouse in which the gene was up regulated developed a tumor. The locations of tumor, in the skull and near the eye, both represented areas of high lactate concentration. In humans, this tumor occurs in skeletal muscle, also associated with high lactate production.

Since 1930, when Otto Warburg first described increased glycolysis (preferential use of sugars) in tumor cells, investigators have pondered the implication of inefficient glucose metabolism in the face of adequate oxygenation.

Human metabolism relies upon mitochondrial function to efficiently liberate the maximum amount of energy in the form of ATP from each glucose molecule. Glycolysis occurring in the cell cytoplasm is highly inefficient and produces only 1/18 of the amount of ATP that a full molecule of glucose can produce through mitochondrial oxidative phosphorylation. Recent molecular biological studies have established that the preferential use of glycolysis may represent the cells need to direct glucose away from energy production and toward the creation of essential structures like amino acids, lipids, and nucleic acids. With the rapid turnover of glucose, cells produce an overwhelming amount of lactate, which is then transported out of the cell. At least this has been the working hypothesis over many years.

More recently, investigators have begun to examine how lactate metabolism may represent the interplay between stromal fibroblast cells and tumor cells. Indeed, many tumor cells are now known to increase lactate uptake reflecting increased lactate production by fibroblasts that have been commandeered in the tumor microenvironment.

Lactate uptake is under the control of a family of transporters known as monocarboxylate transporters, of which nine have been described. These are expressed differently in various tissues, have different affinities for lactate and transport in one direction or another. These processes appear to be under the control of the major regulator of oxygen metabolism known as HIF-1 alpha. As cancer cells adapt to a high lactate environment, they can survive in low oxygen tension.

The preferential use of lactate as a source of energy is contrary to many dictates of current metabolic research that suggest that tumor cells preferentially use glucose and have limited capacity to utilize non-glucose energy sources like the ketone bodies acetoacetate and beta-hydroxybutyrate. Substantial literature on ketogenic diets suggests that these ketone bodies deprive cancer cells of needed nutrition and energy. The current discovery by the Utah investigators, as well as interesting work conducted by researchers in Italy on the prostate cancer, provide a new angle on some of these principles of cancer metabolism.

As the investigators from Utah note, the alveolar soft part sarcoma is a rare tumor, but the implications of these findings could be profound, as they force us to re-think tumorigenesis and the metabolic basis of cancer.

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