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Tumours: “better understanding has improved treatments”

Targeted therapies: new weapons against tumours

Agnès Vernet, Science journalist
On October 21st, 2021 |
4 mins reading time
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Targeted therapies: new weapons against tumours
Philippe cassier
Philippe Cassier
Medical Oncologist at the Léon Bérard Centre
Key takeaways
  • Even though 382,000 new cases of cancer were recorded in France during 2018, the overall survival rate has improved thanks to earlier diagnosis and advances in treatment.
  • Until the 2000s, doctors were looking for molecules that destroyed cancer cells without always knowing how they worked, but now targeted treatments are being established in a more rational and systematic manner.
  • Tumours differ from one another so targeted therapies accompanied by effective diagnostic tools are used to check that the right target is indeed present in the patient.
  • New anti-cancer drugs are the result of this change in approach and these treatments can have spectacular effects – although tolerance can still be an issue.

In France, more than 300,000 peo­ple are diag­nosed with can­cer each year with 382,000 new cas­es record­ed in 2018, accord­ing to Inca. That same year, 157,400 deaths were attrib­uted to can­cer. How­ev­er, the data shows that this fig­ure is falling thanks to ear­li­er diag­no­sis and ther­a­peu­tic advances, par­tic­u­lar­ly for the most com­mon can­cers. These advances include tar­get­ed ther­a­pies based on a new drug devel­op­ment strat­e­gy. “Where­as con­ven­tion­al chemother­a­pies were pre­vi­ous­ly devel­oped using a more empir­i­cal approach, tar­get­ed treat­ments are now being estab­lished in a more ratio­nal and sys­tem­at­ic man­ner,” explains Philippe Cassier, med­ical oncol­o­gist at the Leon Bérard Cen­tre in Lyon.

Until the 2000s, we were look­ing for mol­e­cules that destroyed can­cer cells, with­out always know­ing how they worked. Nowa­days, how­ev­er, progress in our under­stand­ing of the mech­a­nisms involved and the con­tri­bu­tions of mol­e­c­u­lar biol­o­gy have changed researchers’ vision. The doc­tor con­tin­ues, “it is now pos­si­ble to iden­ti­fy a tar­get, a key stage in the devel­op­ment of tumours, and then to look for mol­e­cules capa­ble of act­ing on it – a rad­i­cal change in the approach to drug development.”

Target tumours

New drugs tar­get bio­log­i­cal mech­a­nisms that are impor­tant for tumour growth, which is hard­er than it may seem because tumours are very diverse. So, from patient to patient, tumours do not nec­es­sar­i­ly depend on the same bio­log­i­cal process­es mean­ing that tar­get­ed ther­a­pies need­ed to be accom­pa­nied by par­al­lel progress in diag­nos­tic tools. “It’s a rev­o­lu­tion at every lev­el of oncol­o­gy,” says Philippe Cassier. Thanks to diag­nos­tic tests, doc­tors can check that the tar­get is indeed present in the patient’s tumour and thus decide whether or not to pre­scribe the treat­ment. These bio­log­i­cal analy­ses iden­ti­fy sig­nals that reflect the mol­e­c­u­lar func­tion­ing of the tumour, known as bio­mark­ers. “Oncol­o­gists must now know how to han­dle bio­mark­ers to know what to pre­scribe the patient,” adds Philippe Cassier. It is becom­ing essen­tial to under­stand the machin­ery of tumour growth if doc­tors are to choose the most appro­pri­ate treatment.

New anti-can­cer drugs are the result of this change in approach. Advances in stud­ies con­cern, on the one hand, the reac­tion of the immune sys­tem to a tumour and, on the oth­er, the mol­e­c­u­lar mech­a­nisms that pro­mote tumour pro­lif­er­a­tion. This has giv­en rise to two new class­es of treat­ments: tar­get­ed ther­a­pies and immunother­a­pies. The lat­ter class of drugs – immunother­a­pies – is the result of an impor­tant dis­cov­ery in immunol­o­gy: tumours exert an immuno­sup­pres­sive action in their envi­ron­ment. “They can manip­u­late the immune sys­tem,” he says. The can­cer thus avoids being attacked by the immune cells that con­stant­ly mon­i­tor the body, able to detect cells that are divid­ing abnor­mal­ly [the defin­ing trait of tumours].

Monitor effects

“Even if our under­stand­ing of the bio­log­i­cal role of the tar­get is incom­plete, clin­i­cal stud­ies in humans will allow us to refine our analy­sis; it is a prin­ci­ple of trans­la­tion­al research,” explains the oncol­o­gist. These devel­op­ments are fuelled by a gen­uine dia­logue between clin­i­cal and basic research. “Observ­ing the effect of the drug on the patient helps to refine our under­stand­ing of its mode of action. Phase I tri­als no longer just allow us to study the tox­i­c­i­ty of the treat­ment, they also estab­lish­es the clin­i­cal-bio­log­i­cal cor­re­la­tion that under­pins its effectiveness.”

These treat­ments some­times have spec­tac­u­lar effects, which has con­tributed to their rep­u­ta­tion as a ‘mir­a­cle’ treat­ment. “This is also true for chemother­a­pies. Some tumours are par­tic­u­lar­ly sen­si­tive to one type of treat­ment, and it is as if they have been giv­en a mag­ic wand,” says Philippe Cassier. As for tol­er­ance, the results are more com­pli­cat­ed than they seem. “With anti-PDL1 immunother­a­pies, the tol­er­ance pro­files are very favourable. But oth­er types of immunother­a­pies, such as CAR‑T cells or neu­tral­is­ing anti­bod­ies, can have seri­ous side effects, jus­ti­fy­ing hos­pi­tal­i­sa­tion in inten­sive care.”

These new ther­a­pies have nev­er­the­less offered new treat­ment options and there­fore increase the chances of find­ing an effec­tive response for each patient. But they have not solved the prob­lem. “Can­cer is a fact of life: we can’t erad­i­cate them entire­ly. It is a dis­ease linked to longevi­ty,” acknowl­edges Philippe Cassier.

Expect resistance

One of the main dif­fi­cul­ties with can­cers is the abil­i­ty of tumours to devel­op resis­tance to treat­ments over time. “This prob­lem is deeply root­ed in the his­to­ry of oncol­o­gy,” explains Philippe Cassier. Clin­i­cal research has tak­en this into account and from which sev­er­al types of response have emerged. First­ly, a solu­tion pro­posed resides in devel­op­ing drugs that are increas­ing­ly spe­cif­ic to tar­gets. “These incre­men­tal advances extend life expectan­cy with­out tumour pro­gres­sion under a giv­en treat­ment. This has par­tic­u­lar­ly been mea­sured in the case of lung can­cers char­ac­terised by a translo­ca­tion of the ALK gene,” explains the Lyon-based oncol­o­gist. Diag­nos­tic progress and sys­tem­at­ic screen­ing pro­ce­dures have also helped to ensure that treat­ment begins increas­ing­ly soon­er. “The ear­li­er the treat­ment is start­ed, the more we min­imise the risk of resis­tance emerg­ing,” explains Philippe Cassier. 

Also, the use of liq­uid biop­sies and blood sam­ples to screen for cir­cu­lat­ing tumour DNA makes it pos­si­ble to iden­ti­fy resis­tance mech­a­nisms more eas­i­ly and ear­li­er than before. Com­bined, these tools con­tribute to improv­ing the man­age­ment of patients suf­fer­ing from can­cer. “These prac­tices are often imple­ment­ed in expert cen­tres. But they are more dif­fi­cult to imple­ment in oth­er care cen­tres, such as pri­vate clin­ics or small­er hos­pi­tals, par­tic­u­lar­ly because of prob­lems relat­ed to cost of these tests,” con­cludes Philippe Cassier. This is main­ly due the way they are reim­bursed, still con­sid­ered in bud­gets for ‘inno­va­tion’ rather than being billed as rou­tine med­ical treat­ments. Resolv­ing the conun­drum of cost and ther­a­peu­tic effec­tive­ness is per­haps the next big chal­lenge for can­cer research.