Pharma Strategy Blog

Genetic Analysis of lung tumours may predict chemotherapy benefit

Canadian researchers concluded that they have identified a 15 gene signature that is an independent prognostic marker in early stage non-small cell lung cancer (NSCLC) for identifying more selectively than stage, patients who may benefit from adjuvant chemotherapy.

The Study

Canadian researchers performed a genetic analysis of frozen, banked tumour samples from 133 patients with early-stage non-small cell lung cancer (NSCLC) to identify a set of genes that could predict whether a patient would benefit from adjuvant chemotherapy.  This was a follow-up analysis from the National Cancer Institute of Canada’s (NCIC) Clinical Trials Group study JBR.10 and was conducted in collaboration with the U.S. National Cancer Institute (NCI).  Of the 482 patients in the original study, tumour samples were available from 133 patients.  Of these patients, 62 had not received adjuvant chemotherapy, and 71 patients received adjuvant chemotherapy.

The results

A set of 15 genes was first identified in the patients who had not received adjuvant chemotherapy. Some of these genes help control cancer cell growth and death or regulate other cancer-related genes. The researchers used this information to classify the tumor samples by risk of recurrence (chance that the cancer comes back after treatment) and found that 31 of the 62 patients had lung cancer with a high risk of recurrence, and 31 patients had lung cancer with a low risk of recurrence.

The tumours from the patients who received adjuvant chemotherapy as part of the JBR10 study were then tested to find the genes that could predict the risk of recurrence.  The patients predicted to have lung cancer with a high risk of recurrence experienced the most benefit from chemotherapy; they were 67% less likely to die from lung cancer than those who did not receive adjuvant chemotherapy.  Adjuvant chemotherapy did not lower the risk of death for patients predicted to have lung cancer with a low risk of recurrence, because the risk of cancer recurrence for these patients was already low.

What this means for patients

According to lead author Ming Tsao:

“Not all patients benefit from chemotherapy, and not all patients require chemotherapy after surgery.  Knowing that a patient may have a more aggressive cancer and that their chance of cure may be improved with adjuvant chemotherapy gives patients and their doctors a clearer picture of the need for treatment after surgery.”

Source:  ASCO Abstract #7510

IGF-1R and it's role in gastrointestimal stromal cancer

Excess amounts of a protein called IGF-1R in patients with gastrointestinal stromal tumours (GISTs) could indicate that the patient may become less responsive to the drug imatinib mesylate (Gleevec), the gold standard treatment after surgery. 

Preliminary studies have shown that GIST cells, especially Gleevec-resistant cells, may respond well to agents in development for treatment-resistant breast cancer, which is marked by excessive production of the IGF-1R protein.  IGF-1R could potentially serve as a marker to identify this subset of GIST patients before therapy begins, when alternative treatments would be most effective.

Researchers at Fox Chase Cancer Center are presenting their findings at the 2008 Annual Meeting of the American Society of Clinical Oncology later this month.

A small percentage of adult gastrointestinal stromal tumours and most pediatric cases, are often less responsive to Gleevec.  They found that tumours in many of these cases coincide with an overabundance of the IGF-1R protein.

GISTs develop through a mutation in the genes c-KIT or PDGFRα, both of which are targets of Gleevec. GISTs without those mutations, known as “wild type,” as well as pediatric GISTs, often do not respond as well to treatment with Gleevec.

The Fox Chase researchers found that, when compared to mutant GISTs, the DNA of wild type and pediatric types exhibited more copies of the IGF1R gene. These tumours also produced many more copies of the IGF-1R protein, which serves to promote cell survival, proliferation and growth in normal cells.  In tumours, an excess of IGF-1R allows cancer cells to grow out of control, breaking the normal control mechanisms that are an inherent part of cell function.  In the laboratory, the researchers found that drugs that decrease IGF-1R activity induced the death of tumour cells.   These studies are the first to reveal the development of wild type GISTs could be related to abnormal expression of IGF-1R.

The next logical step is to test the concept in clinical trials in the appropriate populations.  The good news for small number of patients who become rsistant to Gleevec is that there is hope on the horizon given the number of IGF-1R compounds being tested in the clinic for several different cancer types. 

Hot oncology drugs - what's new at ASCO?

The annual American Society of Clinical Oncology (ASCO) conference begins later this month and the data has just been released.  Here are some key abstracts prior to the presentations:

Eli Lilly’s Alimta (pemetrexed) slowed the spread of non-small cell lung cancer in patients with advanced disease. It’s approved for use in patients who have failed chemotherapy; this study suggests it may be added to treatment earlier in the course of disease.  Lilly are reportedly filing the early data in patients with select histology later this year.  It was recently approved for first-line use in the EU.

Novartis' RAD001 (everolimus); nearly two-thirds of renal cell cancer patients taking had progression of their disease delayed by a year, a significantly better result than in those taking placebo.  The disease did not progress for one year in 65 percent of patients taking RAD001, taken once daily orally, compared to 37 percent in those taking placebo, according to detailed results from a late-stage trial, which was stopped early because it met its main target.

GSK 's Tykerb (lapatinib) demonstrated positive data from the first-ever randomized, multi-center, open label Phase III trial of the combination of two targeted agents, lapatinib and trastuzumab (Herceptin), in women with HER2-positive metastatic breast cancer who had previous been heavily pre-treated with taxanes and anthracyclines.

Genentech's Avastin (bevacizumab) showed improved survival for patients with recurring brain cancer. The Phase II trial compared Avastin with irinotecan chemotherapy to Avastin alone in patients with relapsed glioblastoma multiforme (GBM), the most common and aggressive type of brain cancer.  Median survival was 9.2 months in the Avastin-only arm and 8.7 months in the Avastin and irinotecan arm.  According to historical estimates, only 15 percent of patients with relapsed GBM would be expected to live without their cancer advancing for six months.

ImClone/BMS's Erbitux (cetuximab) new gene findings indicate a simple gene test could allow doctors to predict in advance which patients are likely to benefit from the therapy, ie those without KRAS mutations, since there is evidence that they are more likely to respond to treatment.  The same approach would also apply to Amgen's Vectibix (panitumumab).

How smoking causes cancer

Research has shown that smoking is strongly linked to lung cancer, but a new discovery may help scientists improve treatments for lung disease in the future.

Oregon Health & Science University Cancer Institute (OHSU) researchers have pinpointed a protein that can lead to genetic changes that cause lung cancer. They discovered that the production of a protein called FANCD2 is slowed when lung cells are exposed to cigarette smoke and the protective effect is lost.  Low levels of FANCD2 leads to DNA damage, triggering cancer.  Cigarette smoke curbs the production of 'caretaker' proteins, such as FANCD2, which normally prevent cancer by fixing damage in DNA and causing faulty cells to commit suicide (apoptosis).

FANCD2 is part of a family of proteins involved in an inherited condition called Fanconi anemia. People with the condition are more likely to develop cancers at a young age and have low levels of these proteins.

This interesting piece of science adds to our understanding of why smoking is so deadly.  Smoking is the single biggest preventable cause of cancer and causes nine out of 10 cases of lung cancer, one of the most common forms of cancer globally, with over a million deaths annually.

Sources:

EurekAlert
OHSU
Brit. J. Cancer

New cancer gene discovered

Scientists at the University of Oklahoma Cancer Institute have identified a new gene that causes cancer.  The ground breaking research appeared in Nature’s cancer journal Oncogene.

The gene and its protein, both called RBM3, are vital for normal cell division.  In tumours, however, low oxygen levels cause the amount of this protein to go up dramatically.  This causes cancer cells to divide uncontrollably, leading to increased tumour formation.

Powerful new technology was used to genetically “silence” the protein and reduce the level of RBM3 in cancer cells.  The approach stopped the tumour from growing and led to cell death.  This new technique has now been tested successfully in several types of cancer models such as breast, pancreas, colon, lung, ovarian and prostate.

Most cancers are thought to come from mutations in genes, but this this discovery shows for the first time that too much of the RBM3 protein can cause normal cells to turn into cancer cells.

The RBM3 protein was found in every stage of many cancers and the amount of protein increased as the cancer grew.  The protein helped the cancer grow faster, avoid cell death (apoptosis) and was also part of the process that formed new blood vessels to feed the tumour, a process known as angiogenesis.  Angiogenesis is essential for tumour growth and this new data suggests that targeting RBM3 may be a useful tool against cancer, as shown in the diagram.

It's one thing to demonstrate success in the lab though - the proof of the pudding is what happens in real life.  The next step is, therefore, designing suitable agents to inhibit the activity of RBM3 and clinical trials may begin within 5 years.  Watch this space!

Source:  University of Okhlahoma

When sci-fi becomes reality in cancer?

Scientists at UCSD in California have developed nanometer-sized 'nanoworms' that can travel through the bloodstream without significant interference from the body's immune defense system to become tiny anti-cancer missiles and home in on tumours.  Isn't that amazing?

The nanoworms essentially form spherical iron oxide nanoparticles that join together, like segments of an earthworm, to produce microscopic worm-like structures about 30 nanometers long, or about 3 million times smaller than an earthworm.  The iron-oxide allows the nanoworms to show up brightly in diagnostic devices such as magnetic resonance imaging (MRI), which are used to scan pictures of tumours.

Nanoparticles are usually recognised by the body's protective immune system as foreign, so they are captured, disabled and removed from the bloodstream within minutes. The reason this idea works effectively is due to a combination of their shape and a polymer coating on their surface, allowing the nanoworms to evade these natural elimination processes. They have been shown to circulate in the body of a mouse for many hours.

So what's the point of this cool technology idea? 

Well, if the nanoparticles were mixed with chemotherapy, they could offer doctors the ability to increase the efficacy of cancer drugs by allowing them to deliver the chemo more directly to the tumours, as a sort of trojan horse or stealth technology strategy.  This would potentially decrease the side effects of toxic anti-cancer drugs by limiting their exposure to normal tissues and targeting the tumour cells, where you want them to do their damage. A similar approach might work for HIV infections too, for example.

You've heard of silver bullets, but these nanobullets might be a commonplace sci-fi tool in the not so distant future. If they make chemotherapy or HIV therapies more effective and less toxic, that's no bad thing for patients.

Source:  Cancer Research Center, La Jolla, CA  [Free article download]

IGF-1R in prostate cancer: a good or bad idea?

The idea that prostate cancer can be treated successfully just by blocking the activity of a protein called insulin-like growth factor (IGF-1) has been undermined by two new studies.

IGF-1 blockage is a goal being pursed by a number of drug companies and academic researchers, stimulated by studies showing an association between high levels of the protein and prostate cancer risk. Many efforts are aimed at blocking the receptors for IGF-1 in prostate cancer cells.

IGF-1 is a polypeptide hormone that can influence growth, differentiation and survival of cells expressing the type 1 receptor (IGF-1R).  Previous clinical, epidemiological and experimental studies have strongly implicated IGF-1 as a contributing factor in the natural history of prostate cancer.  There is, however, very little evidence to prove that the expression or activation of the IGF-1 signaling pathway at physiologically relevant levels is sufficient to cause a healthy prostate cell to become a cancer cell.

Without a proof of concept, therapies under development to treat prostate cancer by inhibiting the ability of insulin-like growth factor (IGF-1) to activate its target receptor could have unexpected results especially if a major tumour suppressor gene (p53) is already compromised.

At the Fred Hutchinson Cancer Centre in Seattle, Greenberg et al., conducted a pair of experiments by manipulating gene expression directly in the epithelial compartment of the mouse prostate gland to better understand the role of IGF-1R.  Compared to studies that correlated elevated levels of IGF-1 with the risk of developing prostate cancer, Greenberg's research showed that eliminating IGF-1R expression in an otherwise normal mouse prostate caused the cells to proliferate and become hyperplastic.  Persistent loss of IGF-1R expression ultimately induced cell stasis and death.  Both of these processes are regulated by the tumour suppressor gene p53 that is commonly mutated in human prostate cancers.  It was, therefore, hypothesized that tumours with compromised p53 might not respond predictably to therapies targeting IGF1 signaling.

To test their reasoning they conducted a second experiment by crossing mice carrying the prostate-specific IGF-1R knockout alleles with transgenic mice that develop spontaneous prostate cancer when p53 and select other genes are compromised.  The results were as expected: prostate epithelial-specific deletion of IGF-1R facilitated the emergence of aggressive prostate cancer in the genetically engineered tumour prone mice.

The study was published in the May 1 edition of Cancer Research, and supports a critical role for IGF-1R signaling in prostate tumour development.  It identifies an important IGF-1R-dependent growth control mechanism, according to the authors.

If the predictions hold true, then tumour cells with intact p53 may show the best response to therapy targeting the IGF-1R signal, however when p53 is not functioning normally, response to this therapy may not be as expected and the cancer may proliferate aggressively.

A search of the database for clinical trials registered with the National Cancer Institute found 18 trials in process that use therapies to inhibit IGF-R1.  None of them, however, include the tumour's p53 status as a criterion for recruiting research participants.  These data suggest that it might be an idea to get data on a patient's tumour before treatment and after treatment, and see if the status of p53 shows whether it would respond more or less to IGF-1 treatment.

The other study, led by Cohen et al. at UCLA, also used mice bred to develop prostate cancer, with some also bred to lack IGF-1 receptors. The research was based on the idea that conventional wisdom suggests that without the IGF receptors, the tumours would fail to develop or be much smaller.

What actually happened was that they were not reduced in size; in fact, they were exactly the same size. Low IGF-1 levels in the mice were accompanied by higher levels of growth hormone and insulin, which stimulated growth of the cancer cells.

Ultimately, these studies do not suggest that IGF-1 blockage is doomed as a treatment, but rather it shows the need for targeting multiple pathways.  As the cancers find ways to overcome IGF-1 blockage, it could be used in conjunction with other therapies.

Earlier detection of cancer using proteomics

Consider that cancer is basically a disease of altered proteomics (proteins), where deranged, hyperactive, or dominating protein signal pathways may drive cancer survival, growth, invasion, and metastasis.  Pathogenic alternations in protein networks extend outside the cancer cell to the tissue microenvironment, in which exchange of cytokines, enzymes, enzyme inhibitors, motility factors, and adhesion molecules act to the advantage of the tumour cell.

Smart particles of polymer gel that can therefore sieve rare proteins from the blood could allow cancer to be diagnosed at an earlier stage.  Researchers looking for ways to make earlier diagnoses of cancer have been  concentrating on finding new biomarkers or molecules indicating the presence of tumours before any symptoms show.

Among the top candidates are small proteins that tumours release into the blood.  The trouble is that these are present in only minute quantities and so get masked by larger, more common blood proteins, such as albumin.  It is possible to strip the larger proteins from blood samples, but this tends to remove biomarkers as well, because they often bind to the larger proteins.  The particles, about 1 micrometre in diameter, solve the problem by removing a particular biomarker from blood, and leaving any large proteins behind.  They do this because they can be "baited" with different chemicals that allow them to trap only certain types of proteins.

Scientists at George Mason University have been working on refining the technology.  They have developed techniques using protein gels consisting of hydrogel particles.  These hydrogel particles, combined with the use of mass spectrometry to isolate the aberrant proteins being pumped out by the tumour at an early stage, may help to identify either early tumour proliferation or progression.

Last year, the group showed that their baited particles selectively pulled small proteins out of test solutions (Nano Letters, DOI: 10.1021/nl072174l). Now they have used the nanoparticles to extract a known cancer biomarker from samples of blood serum and have proven the concept.

At the American Association for Cancer Research meeting last week, Luchini described how the researchers spiked serum with traces of platelet-derived growth factor (PDGF), bound to albumin.  PDGF is a biomarker associated with growth of the blood vessels that feed a developing tumour.  The hydrogel particles removed the biomarker from its albumin carrier and concentrated it from levels that were previously below the limits of detection.  The particles also protected PDGF from attack by a protein-digesting enzyme, which is important because blood contains similar enzymes.

The ultimate payoff of clinical proteomics will be to go beyond molecular discovery to reach individualised therapy.   Just as patients visiting an oncologist’s office are distinct individuals, with no two being exactly alike, it is likely that their respective tumours have unique molecular patterns, even though they may be given the same pathological description.   Individualised therapy in this concept would mean treating patients by the particular mutations, or protein aberrations that their tumour expresses, with the goal of having appropriate therapy which offers the most optimised response.