MYC, a gene with high cancer-initiating potential, is
overexpressed in over 40% of breast cancers. While MYC programs breast cancer
cells to build more macromolecules (anabolic metabolism) it also creates a
metabolic vulnerability by making them more sensitive to a type of cell death
known as apoptosis. Research Director Juha Klefstrom, PhD, University of
Helsinki, Finland, has worked for a long time to exploit this apoptosis-sensitising
effect of MYC in the battle against the cancer.

Klefstrom and his research group found that, because of this
vulnerability, cancer cells can be attacked with a “drug cocktail”
that includes the diabetes drug metformin and venetoclax, a BCL-2 protein
inhibitor that can induce apoptosis in cancer cells. The group identified
metformin in a search for drugs that could boost the apoptosis-inducing action
of venetoclax. Venetoclax has been approved to treat certain leukemias but not
yet for the treatment of breast cancer.

“This drug combo exploits specific metabolic vulnerabilities
that high levels of MYC creates in tumour cells. Metformin and venetoclax, when
given together, killed breast tumour cells in culture and blocked tumour growth
in breast cancer animal models. Furthermore, the drugs efficiently killed
authentic breast cancer tissue donated by breast cancer patients. The breast
cancer samples were obtained fresh from surgeries performed in Helsinki
University Hospital”, Dr. Klefstrom says.

However, the researchers soon discovered that the metformin
plus venetoclax treatment only held tumours in check as long as the mice with
implanted breast tumors were actively being treated with the drugs; once the
treatment was stopped, the tumours grew back. The study shows that tumours were
initially filled with tumour-killing lymphocytes; however, after the treatment
they largely vanished and the remaining killer cells expressed PD-1, a marker
of immune cell exhaustion.

To help the immune cells better fight the tumour, the
researchers developed a new treatment strategy. First, they hit breast tumors
with apoptosis-inducing drugs metformin and venetoclax to reduce the tumour
size and to wake up killer lymphocytes. After the primary tumours were
surgically removed, the mice were then treated with a triple combination:
metformin, venetoclax and a PD-1-targeted antibody, which is used in
immunotherapies to keep killer cells active long-term.

“With this combination the survival of mice carrying
implanted tumours was extended dramatically in comparison to mice that were
treated with only single or double combinations”, Klefstrom states.

Klefstrom highlights that this is a wonderful example of a
translational study fundamentally aimed at taking research from bench to
bedside. The key people from the University of Helsinki and Helsinki University
Hospital (HUS) – basic researchers, pathologists, surgeons and oncologists –
were all involved at the earliest stages of the study.

The first author of the study Dr Heidi Haikala notes: “It’s
quite amazing how we’ve been able to bring a discovery from the lab bench all
the way to the doors of the cancer clinics within the time frame of one PhD
project. We are very excited about our findings and hope that they will
translate to benefit breast cancer patients.”

“We finally have a drug combination that efficiently exploits
MYC’s apoptotic function and most importantly, these drugs can be tested in the
clinic in real patients. We are currently working hard towards this next
step,” Klefstrom concludes.


Reference: Klefstrom
J, et al. Pharmacological reactivation of MYC-dependent apoptosis induces
susceptibility to anti-PD-1 immunotherapy. Nature Communications. Published 6
February 2019.