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Molecular mind-set: How we are completely rethinking cancer

September 10, 2018

Oncologists are increasingly understanding the genomic drivers behind cancers, leading to a host of promising new treatments.

Cancer treatments have traditionally focused on where they originate in different parts of the body – the lung, the stomach, the breast. But recently, oncologists have increasingly been looking at the disease from a different angle – a more molecular one.

A six-year long study by the Pan-Cancer Initiative suggests that cancers originating from the same tissue can have very different genomic profiles, but cancers that start in different organs can actually share commonalities at the molecular level. The results showed that based on their cellular and genomic makeup, and independent of their anatomic site of origin, cancer types could be re-classified into 28 different molecular types, or ‘clusters’.1

The study found that almost two-thirds of these clusters were found in more than one part of the body. In fact, one particular cluster was found in 25 different tumor types around the body.

Historically, these cancers would have been treated in different ways. But now, looking at cancer at a molecular level rather than where they first develop could have a profound impact over how we treat it.

“It’s time to re-write the textbooks on cancer,” says Christopher Benz, Buck Institute for Research on Aging in California, “It’s time to break down the silos in clinical oncology that make it difficult for patients to take advantage of this paradigm shift in cancer classification.”

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Passengers and drivers

Cancer is a disease in which cells keep dividing and growing uncontrollably, typically through genomic alterations in specific genes. Most normal cells undergo apoptosis (programmed cell death) as a controlled part of an organism's growth. But the genomic alterations in cancer cells mean these mutated cells survive and multiply instead.

While genetics deals primarily with how one trait gets passed along from parent to child, genomics looks for any potential defects or alterations that may have occurred by analyzing the entirety of genes (the genome) in a cell. Advances in DNA and RNA sequencing over the past decade have made it possible to systematically study these genomic changes. To look at the cell and try and identify what specific processes and signaling pathways have caused it to mutate.

“This is the power of precision medicine. Overlaying the multiple technologies and tools to get a complex signature of the cancer and target it specifically, that's the reality of the future.”

– Dr. Patricia Carrigan, head of Regulatory Affairs Companion Diagnostics Oncology at Bayer

Not all genomic alterations, however, affect the same things. Some drive the growth of the tumor while others are passengers, results of the underlying genetic instability of the cancer that are just along for the ride.

Through increased sequencing, oncologists are seeking to better identify these drivers and find commonalities. By doing so, they can seek to develop drugs that can more accurately target different tumor types in more effective ways.

The power of precision medicine

Over the last decade, the cost, speed and accuracy of DNA and RNA sequencing has changed dramatically. Technological advances in next-generation sequencing (NGS), as current genetic sequencing is known, have made it both cheaper and more sensitive. This is enabling oncologists to build a far more detailed picture of the molecular makeup of an individual patient’s cancer, and treat it accordingly.

“By having the tools such as next generation sequencing we're able to look for biomarker signatures that will differentiate patients who should respond to a drug versus those who will not,” says Dr. Patricia Carrigan, head of Regulatory Affairs Companion Diagnostics Oncology at Bayer. “This is the power of precision medicine. Overlaying the multiple technologies and tools to get a complex signature of the cancer and target it specifically, that's the reality of the future.”

And this combination of understanding both a patient’s individual cancer at a molecular level and the potential oncogenic drivers that could be causing it, have led to the development of an array of groundbreaking cancer treatments.

Tackling tumors with a new toolkit

For the past thirty or so years, the oncologist’s toolbox has primarily comprised radiotherapy, chemotherapy, and surgery to remove tumors. We are now utilizing far more targeted therapies.

Each precision treatment looks at tackling the tumor in a different way:

  • CRISPR-Cas9 genome editing technology2 is being used to edit the specific genetic alterations driving cell mutation.
  • T-cell treatments are a type of immunotherapy3, which involve taking a patient's own immune cells, the white blood cells called T-cells, and reprogramming them to attack the tumor.
  • Biologics4 are a class of drugs based on large protein molecules that bind to specific cell surface proteins such as receptors that are associated with the disease process. 
  • Small molecules are active-ingredients and represent the overall majority of drugs used today. Most work by interfering with certain proteins in cells that are associated with the disease process. Scientists are now developing highly selective compounds that have the potential to treat the cancer by directly inhibiting a tumor’s driving molecular alteration.

While many of these treatments are still at preclinical and clinical development stage, early results suggest they could ultimately change how we combat cancer in the future. One example of this is the small molecules research being done by Bayer and Loxo Oncology. The companies are developing two novel agents which, once approved, might help doctors provide a specific treatment for patients who have certain genomic alterations in their tumor cells.

“Changing mindsets in oncology from tumor-specific to genome-specific is starting to happen,” says Dr. Marc Fellous, global medical lead at Bayer. “Developing new tumor-agnostic drugs might allow us to bring treatments that require the identification of genomic alterations into the mainstream consciousness.”

For this to happen, and for precision medicine to become the norm, genomic sequencing needs to increasingly become part of a patient’s diagnosis. The better we understand cancer at molecular level the closer we can get to a cure.

Footnotes

  1. Hoadley, K. et al. Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer, Pan-Cancer Initiative http://www.cell.com/cell/abstract/S0092-8674(18)30302-7
  2. Ratan, Z. et al. CRISPR-Cas9: a promising genetic engineering approach in cancer research https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802696/
  3. CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers, National Cancer Institute https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
  4. Small and large molecules, Bayer Pharmaceuticals http://pharma.bayer.com/en/innovation-partnering/technologies-and-trend…
 

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