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| Dr Luciano Martelotto |
Collaborative research including Monash University has uncovered the
principles behind why some tumours may become resistant to targeted therapies,
paving the way for new and more effective cancer treatments.
Published last week in Nature Medicine, a team of researchers including
Dr Luciano Martelotto from the School of Clinical Sciences at Monash Health
(SCS) in collaboration with Dr Piro Lito’s laboratory at the Memorial Sloan
Kettering Cancer Center, New York, have found a mechanism that explains why and
how resistance to therapy occurs in certain cancers, and identified types of therapies to prevent this process from occurring.
Lead author Dr Martelotto said that until now, the way that tumours
respond and become resistant to therapies has been poorly understood.
“In our study, we generated models of melanoma and lung patients’ tumour
cells and used modern DNA sequencing technologies to examine the genetic
information of many individual malignant cells to better understand how tumour
DNA changes in response to therapy,” Dr Martelotto said.
“This is important because it helps explain how these changes in the
genetic material help the cancer escape the effects of the treatment.”
“For the first time, we’ve demonstrated that solid tumours like melanoma
and lung cancers can grow back shortly after therapy, but when they do they are
made of genetically diverse sub-groups of malignant cells—and, scarily enough,
all of these are resistant to treatment. This genetic diversity is what allows
the cancers to adapt to the treatment and resist it.”
The research team used their results to create a hypothetical model of
resistance (called a fitness threshold
model), enabling
them to understand how the resistance mechanism works.
“We knew that drugs targeting different parts of the same cellular
pathway have distinct mechanisms and, as a consequence, we proposed that they
should also exert different selective pressures on cancer cells,” Dr Martelotto
said.
The research team’s fitness threshold model links the effect of a
given drug with the selection of resistance-causing alterations in DNA,
resulting in significant implications for the treatment of cancer patients.
“We’ve now shown that sequentially treating tumours with drugs that
neutralise different parts of the same pathway is ineffective; however, when
the drugs are combined and administered in an intermittent regime, the treatment becomes
highly effective and without apparent toxicity,” Dr Martelotto said.
Dr Martelotto said that these findings are important for oncologists and
patients because they show that the way that drugs are administered during
therapy can have a critical impact on the outcome of the response to treatment.
“In our work, we showed that intermittent administration enables simultaneous delivery of multiple targeted
therapies while maintaining lower
toxicity, and our fitness threshold model explains how other
resistance-causing alterations may develop during targeted therapy,” Dr
Martelotto said.
This important finding sheds light into the development of new therapeutic designs to more effectively treat patients.
