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Main Story
The Battle Continues
The days for an oncologist to prescribe chemotherapy for
all cancer patients are numbered. With the alarming rates of cancer incidence,
more and more treatment candidates are in the cancer kitchen, lending immense
promise to the future of personalised cancer treatment. Divya Pamnani
provides an insight into translational cancer research
 The
reality about medicine is that one size doesn't fit all. Therapy focus is witnessing
a shift to treating the causal pathway of disease and not merely the symptomology.
The blunderous approach to cancer treatment in the 1950s was to wreck DNA and
stopping replication, which created havoc for healthy cells, notably in the
gut, bone marrow, mouth and hair follicles, resulting in grossly unpleasant
toxicity profiles. The 1990s ushered in the era of cancer biology, identifying
cellular processes and molecules unique to cancer cells. Research has come a
long way since the 50s and 'personalised medicine' is certainly the buzzword
of the 2000s. The reason is that chemo, surgery and radiotherapy rarely get
rid of every single microscopic cancer cell and lastly rogue cancer cells find
ways to elude even the newest of targeted treatments including Avastin, Herpceptin,
Gleevec, Gefitinib and Erbitux. The biotechnology industry is emerging as a
hub of innovation for cancer biomarkers, which are critical for the rational
incorporation of targeted therapies into treatment. Further, the identification
for New Chemical Entities (NCE) or New Molecular Entities (NME) are also flooding
the research pipeline, which are drugs that contain no active molecules previously
approved by the Food and Drug Administration (FDA). Large pharmaceutical companies
are coming under pressure and are forced to implement creative R&D strategies
and sourcing innovative new molecules. The reasons for this are manifold. First
off, the maximisation of blockbuster revenues is being compromised by the introduction
of generics at lower prices leading to price erosion. Secondly, the role of
chemotherapy and radiotherapy in treatment is almost reaching saturation leaving
minimal scope for improvement. Lastly and most importantly, the alarming increase
in cancer incidence and the reality about the heterogeneity of the disease emphasise
the need for novel therapeutics to actually make it into the hands of patients.
The Stem-cell Debate
For years cancer biologists have known that the biggest threat in cancer is
posed by metastatic cells, which are known to be responsible for 90 per cent
of all cancer deaths. After decades of research on the war against cancer, biologists
are finally coming to the point, in the quest to find answers to the 'why' of
cancer metastasis. The last decade or so has seen the surfacing of a new paradigm
in the terms of therapeutic strategies which may be available to target cancer.
This is based on the established consensus among cancer biologists that not
all cancer cells are the same. Essentially, there exists a hierarchy of cells
inside a tumour, and it's a select few cells, called cancer stem cells, that
are capable of generating new tumours. Such tumour-budding cells have been implicated
in many cancers, including those of the colon, leukemias, lymphomas, head and
neck, brain, and breast. "These cells are thought to play a critical role
in resistance to conventional treatments like chemotherapy and radiation and
also with cancer recurrence after treatment," explains Dr Indraneel Mittra,
Department of Surgical Oncology and Research, Sir Ganga Ram Hospital. Earlier
this year, a team of researchers at Harvard implicated cancer stem cells in
the speed with which the disease progresses in humans. The proteins associated
with these stem cells conferred speed of cell proliferation to the tumor. The
team is currently in the process of developing an antibody targeting the cancer
stem cells, having achieved initial success of decelerating tumor growth in
mice.
Many researchers believe that selectively targeting cancer stem cells and thus
attacking the disease at its root holds a lot of promise in the future. Most
current therapies target the bulk of the tumour cells, while the cancer stem
cells are left behind. Obviously, tumour eradication is superior to tumour arrest,
which is why proponents of the cancer stem cell hypothesis predict that targeting
cancer stem cells is going to be very important in the future of cancer treatments.
“The evidence for cancer stem cells is building, slowly but surely. Already
a number of cancer stem cell targeting candidate drugs are currently in stages
of early research at major medical centers in the US, a few of which have entered
Phase I clinical trials," informs Dr Sewa Legha, Clinical Professor of
Medicine and Oncology-Baylor College of Medicine & Director - Melanoma Center,
St Luke's Episcopal Hospital, US. On the other hand, skeptics of the cancer
stem cell hypothesis question its credibility. They elucidate that the stem
cell hypothesis can only hold true if these cells make up a small fraction of
the tumour mass. Evidence from studies show that according to pre-established
molecular marker criterion, the so-called 'stem cells' make up 10 per cent to
40 or 50 per cent of the tumour. So, if a treatment shrinks the size of the
tumour by 99 per cent, then the stem cells must also have been susceptible.
Skeptics also raise questions about the research done on mice. They say that
the same cells that gave rise to tumours transplanted into mice might not necessarily
give rise to tumours elsewhere, which questions by definition whether they are
stem cells or not. In concurrence with the skeptics, Dr Mittra concludes that
"It is too early to judge as to whether they indeed play a key role in
the evolution of cancer, and as to whether stem cells can be used in the future
as treatment targets".
Hence, there are two sides to the cancer stem-cell debate.
Whilst the proponents of this theory are all charged up to direct their research
to treat cancers that are deemed incurable by tackling the root of the problem,
the skeptics need more questions to be answered to be convinced.
 What
do researchers actually have to show for the billions of dollars being spent
on cancer research? Not much, if Food and Drug Administration (FDA) statistics
are an indication. For other diseases, about 20 per cent of new compounds
arising from basic biological discoveries are eventually approved as drugs
for patient use. For cancer, an abysmal 8 per cent make the cut. "There
is a realisation that in spite of huge investment in basic research of cancer
biology the fruits of research are not really reaching the patients"
explains Dr Indraneel Mittra Department of Surgical Oncology and Research,
Sir Ganga Ram Hospital. "There is often a disconnect between the basic
science research of the mechanisms leading to cancer and the efforts to
actually control it. It only makes for elegant science and important research
papers," he adds. Tumour shrinkage is good, but what about the 'real
cure?' What about translating research from the 'bench to the bedside?'
The pressure is escalating to make it happen for cancer. Dr Mittra makes
a case for the need for better collaboration between scientists and the
clinicians, or, conversely, the exploitation of ideas generated in clinics
that could be used in the labs successfully, to generate revolutionised
diagnostic and therapeutic strategies. Essentially, the need of the hour
is that the often disparately inhabited worlds of the basic-science cancer
research and the efforts to control the disease, need to collide. |
Biomarkers
Cancer biomarkers, usually proteins released in the blood
from tumour cells, are making way into the world market for In Vitro Diagnostic
(IVD) tests for cancer. Cancer bio-markers, or tumour markers, have been in
use for several decades in cancer diagnosis and prognostication. Tumour markers
have been used for cancer detection, as well as in monitoring the progression
of disease thereby making early therapeutic intervention possible. "The
current wave of research in biomarkers is based on molecular biological approach
to identify cancer markers. Many areas of research are being pursued that mainly
include searching for mutated genes or receptors derived from cancer cells in
the blood," informs Dr Mittra. The reasons include the need for effective
screening for early diagnosis and disease prevention, and the developmental
role of such diagnostics in pharmacodiagnostics, which are essential in matching
the right treatment to the patient and monitoring of the disease. Cancer biomarkers
are essentially of three types - prognostic, predictive and pharmacodynamic.
Prognostic biomarkers can be used for prognosis, to predict the natural course
of a tumour, indicating whether the outcome for the patient is likely to be
good or poor. Predictive biomarkers, as the name suggests can aid doctors by
predicting about how patient will respond to a given drug and pharmacodynamic
biomarkers can help in deciding what dose might be most effective. "In
principle, biomarkers should improve patient outcomes by ensuring that each
patient receives the drugs that are most likely to be effective for his or her
particular tumour, thereby enhancing the drug response rate and limiting toxicity,"
believes Dr Legha. In addition to improving the effectiveness of therapy, biomarkers
have the potential to improve the cost-effectiveness of treatment, both by avoiding
the use of costly therapies to which a cancer will not respond and by avoiding
the need to manage associated side effects of such treatments. The good news
is that predictive biomarkers are already making waves in treatment. "Biomarkers
are effectively being used in diagnosis and management of certain types of cancers.
For example, Prostate Specific Antigen (PSA) secreted by prostate cancer cells,
has been used to screen the general population to identify patients with early
cancers with some success," elucidates Dr Mittra. Further, patients with
breast cancer in which the gene Epidermal Growth Factor Receptor (EGFR) is amplified,
benefit from treatment with trastuzumab (Herceptin) vs. tamoxifen. Similarly,
patients who have leukemia with the Philadelphia chromosome translocation respond
to imatinib mesylate (Gleevec or Glivec). Distinct mutations in patients with
chronic myeloid leukaemia who develop resistance to Gleevec, predict differential
sensitivity to the newer drugs Dasatinib and Nilotinib. The list is long, but
the point is that biomarkers are helpful. The bad news is that biomarkers in
cancer still have a long way to go. "These tests may produce false positive
or false negative results causing unnecessary anxiety and investigations"
reasons Dr Mittra. Consequentially, this will lead to many benign tumours being
biopsied and many that will harbour malignancies long enough to metastasise.
Further, many cancers are far more difficult to detect, so discovering biomarkers
for such cancers is still a far cry. "On the whole, tumour markers have
had a definite role to play in the management of a handful of cancers. The future
will tell whether they will be clinically useful," says Dr Legha.
Shedding Light on the miRNA
 "Prostate
Specific Antigen (PSA) secreted by prostate cancer cells, has been used
to screen the general
population to identify patients with early cancers with some success"
- Dr Indraneel Mittra
Department of Surgical Oncology and Research
Sir Ganga Ram Hospital
New Delhi
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Researchers have recently discovered hundreds of small, non-coding
RNAs called microRNAs (miRNAs) that are involved in controlling expression of
genes throughout eukaryotic genomes - the full set of chromosomes in gamete
cells. These single-stranded RNA sequences are produced endogenously and are
perceived to be revolutionising both basic biomedical research and drug discovery.
Approximately three per cent of human genes encode for miRNAs and upto 30 per
cent of human protein coding genes may be regulated by miRNAs. There are more
than 500 known miRNAs encoded by the human genome and each is thought to target
up to hundreds of messenger RNAs. Unlike the more familiar messenger RNA (mRNA),
transfer RNA (tRNA) and ribosomal RNA (rRNA) - molecules that directly mediate
protein expression by being involved in amino acid assembly, these miRNAs are
not directly involved in protein synthesis. Essentially, they do not code for
specific proteins, but instead are extremely important in gene expression, emerging
as pivotal cellular regulators that serve widespread functions in the regulation
of cell differentiation, cell proliferation and cell death. miRNAs function
through post-translational degradation of mRNA or inhibition of protein translation.
This post-translational suppression of gene expression is achieved through binding
to the complementary sequence of target mRNA. This binding event causes translational
repression of the target gene and also stimulates rapid degradation of the target
transcript. Research in animal models has shown that malignant tumours and tumour
cell lines have widespread de-regulated miRNA expression compared to normal
tissues. Research in human cancers has lead to the observation that there is
a global decrease in miRNA in tumours, indicating that small RNAs may have an
intrinsic function in tumour suppression. However, the question remains whether
the altered miRNA expression observed in cancer is a cause or consequence of
malignant transformation. These observations have lead researchers to believe
that miRNAs and their global decrease in the body can play a role in the detection
of cancer. Essentially, miRNA profiling can play a part in cancer diagnosis.
The Biomarker-miRNA Combination
The existence of miRNAs and their dysregulation in cancer
are recent discoveries for cancer biologists. Research in animals such as worms
and flies showed that some miRNAs have specific expression in certain kinds
of cells and not anywhere else. This could essentially mean that circulating
miRNAs can serve as cancer biomarkers for a variety of common cancers. This
research shows that microRNAs, which weren't previously thought of as markers
of cancer in the blood, are now a worthwhile class of molecules for the purpose
of early cancer detection. Furthermore, there already exists a powerful tool
like Polymerase Chain Reaction (PCR) technology to characterise and detect miRNAs.
An even more recent discovery is that miRNAs circulate outside cells and are
amazingly stable. Researchers at Hutchinson Center's Human Biology and Clinical
Research division, Seattle, were surprised to find miRNAs in the circulating
plasma and serum, not degraded by enzymes of the blood that would normally degrade
regular RNA. This has lead researchers into a new direction of determining whether
cancer-associated miRNAs could be found. "This is really a very new field.
Research has suggested the role of miRNAs in carcinogenesis, however, much more
work needs to be done to clarify its role in cancer initiation, progression
and diagnosis," sums up Dr Mittra.
Macro Future of the Micro Environment
Another exciting opportunity involves the environment around a tumour cell.
The micro-environment in which a tumour originates plays a crucial role in cancer
initiation and progression. Recent studies indicate that the tumour microenvironment
is unique in providing both supportive and inhibitory factors which determine
the fate of the tumour and its host. Earlier, the focus was on the cancer cell.
Researchers believed that by studying the genes inside the cell, they could
understand everything that was going on. But now, research studies have suggested
that many tumours are governed by signals they receive from outside. Researchers
believe it is the combined interaction of signals inside and outside the tumour
that lead to aggressiveness and eventually metastasis.
There is a lot of research done along the lines of natural compounds and non-drug
interventions such as stress reduction to keep the microenvironment inhospitable
to cancer. Cancer cells have receptors that remove stress hormones out of the
bloodstream and use them to increase angiogenesis, which is the process whereby
the tumour increases its blood supply to nourish its growth. Though hard to
quantify, researchers at MD Anderson Cancer Center in Houston explain that it's
a complicated mix of diet, exercise and stress reduction approaches that can
keep the tumour micro-environment hostile to cancer.
In conclusion, cancer researchers are making exciting breakthroughs. Cutting
edge techniques are allowing the identification of experimental drugs quicker
than ever before. With a growing body of knowledge about the molecular mechanisms
of cancer, different pathways, biomarkers detecting the mutations involved and
targeted therapies, researchers are making big leaps in attempts to streamline
treatments, ushering in the era of personalised medicine. "An enormous
investment has also been made in determining the risk of developing cancer in
an individual by genome wide analysis of certain mutations. This approach may
add to the list of known risk factors, and thereby refine our ability to identify
persons at higher risk of certain cancers" explains Dr Mittra, agreeing
that blocking cancer's aberrant pathways is the key. The leading edge of research
in personalised medicine today is determining how a particular patient's tumour
cells work, and targeting those very pathways, simultaneously or sequentially.
To keep with the spirit of optimism, let's hope that such findings will not
join the long list of interesting discoveries irrelevant to patients.
pamnani.divya@gmail.com
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