The Scientist - USA (2022 - Spring)

36 THE SCIENTIST | the-scientist.com

are in place to preserve the genomic integrity of the organ-

ism, and they usually work. In cancer, however, they are often

breached. Understanding how cancer cells cope with deleteri-

ous consequences of CIN could result in an important thera-

peutic opportunity.

Indeed, there has been a burgeoning interest in understand-

ing and undermining cancer cells’ ability to tolerate CIN. Mul-

tiple academic groups have recently tackled this question using

genetic screens, and some have identified genes and cellular pro-

cesses whose loss is selectively lethal to cancer cells with high

levels of CIN. One such target is a kinesin protein called Kif18a,

which plays a role in chromosome movement during mitosis and

was independently found by three groups to be required for cell

division in cancer cells with CIN but not those without.13-15 Inter-

estingly, mice lacking functional Kif18a are viable with mini-

mal defects, suggesting that targeting this kinesin might indeed

provide a valuable and safe therapeutic. A Phase 1 clinical trial

sponsored by Amgen is now testing Kif18a inhibition in patients

with advanced cancers.

Another therapeutic strategy that has been explored by a number

of academic groups, including our own, is the inhibition of targets

that enable cancer cells to cope with chronic inflammation. ENPP1,

for example, was initially identified by Harvard Medical School’s

Timothy Mitchison and Stanford University’s Lingyin Li (then at

Harvard),^16 and found by my group to be selectively upregulated in

chromosomally unstable cancer cells.^17 ENPP1 is an enzyme located

at the outer surface of cancer cells; it degrades an immune stimula-

tory metabolite called cGAMP that is produced when cGAS encoun-

ters DNA in the cytoplasm of tumor cells. If left intact, cGAMP

can spread between cells and initiate a robust antitumor immune

response. By degrading this molecule in the extracellular space, can-

cer cells prevent immune cells from sensing the inflammation that

arises from CIN, thus providing them with much-needed cover. Not

only does this shield tumor cells from attack by the immune system,

but the breakdown of cGAMP ultimately generates another metab-

olite, called adenosine, that promotes immune cell dysfunction and

enhances the ability of cancer cells to migrate. This was an eye-

opening example of how cancer cells can turn a foe (cGAMP) into a

friend (adenosine), thus bending inflammation to their own benefit.

To augment these and other approaches, researchers at Volas-

tra, where I continue to serve as a scientific advisor, are pursuing

a deep and fundamental understanding of the biology of CIN. Out

of this research, which involves both computational and genetic

screens that can inactivate individual genes one at a time, a number

of therapeutic strategies have emerged. The company’s lead drug

candidate targets microtubule attachments to chromosomes and

is selectively lethal to cancer cells with CIN while sparing normal

cells; Volastra plans to advance this one to clinical trials in 2023.

Additional treatment strategies we’re exploring include modulating

mitotic spindle formation, altering chromosome organization dur-

ing cell division, and harnessing CIN-driven inflammation.

Identifying targetable pathways linked to chromosomal insta-

bility is exciting, as it creates an opportunity to therapeutically

intervene to tackle a feature of cancer that was hitherto consid-

ered undruggable. CIN is a particularly attractive drug target

because it is only present in cancer cells, meaning CIN-targeting

therapies should selectively kill cancer cells while sparing normal

cells—the holy grail of cancer therapy. The progressive rapproche-

ment among the fields of cell biology, genomics, and cancer biol-

ogy over the past decade will fuel novel discoveries that can only

be made through a multidisciplinary approach as well as robust

collaboration between academia and industry. The ultimate goal

is to serve patients, such as mine who developed brain metastasis,

for whom there are currently very limited therapeutic options. g

Samuel F. Bakhoum is a physician-scientist and cancer biologist

at Memorial Sloan Kettering (MSK) Cancer Center in New York

and cofounder of cancer therapeutics company Volastra Thera-

peutics, in which he continues to hold intellectual property and

other financial interests. MSK also has intellectual property rights

and associated interests by virtue of licensing agreements between

MSK and Volastra Therapeutics.

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