Blood's corrupt endothelial cells protect blood cancer cells from chemotherapy

Researchers at Weill Cornell Medical College found that endothelial cells (cells that line blood vessels) that grow with leukemia cells are destroyed and rescue cancer cells
under the action of chemotherapy drugs.

There is growing evidence that genetic mutations are not enough to cause cancer; Tumor cells also need a suitable environment
for growth.
The new study, published Aug.
18 in the journal Blood, found that endothelial cells protect T-cell acute lymphoblastic leukemia (T-ALL) cells from damage from chemotherapy drugs that would otherwise kill cancer cells
.
T-ALL cells cause an aggressive form of blood cancer
.
The discovery and the platform they use could improve the way scientists find
and test new drugs to treat the disease.

"We have discovered that endothelial cells play a new role in T-ALL," said co-senior author Giorgio Inghirami, Ph.
D.
, professor of pathology and laboratory medicine and a member of
the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical School.
"Our platform has the potential to lead to more effective drug discovery programs and better clinical trials
.
"

Dr.
Inghirami said about 30 percent of patients with T-ALL do not respond to chemotherapy, and some patients who are successfully treated relapse
years later.
It can be a very difficult experience
for patients and their families.

Previous studies have suggested that stromal cells in the bone marrow may play a role in blood cancers, but no one has studied the cells
lining blood vessels.
So Dr.
Inghirami, in collaboration with study co-senior author Shahin Rafii, Ph.
D.
, head of the Department of Regenerative Medicine and director of the Weill Cornell Medicine Hartman Institute for Organ Regeneration, developed a method
to study the effects of chemotherapy on the growth of T-ALL and endothelial cells together.
They developed a preclinical model
using tumor cells from T-ALL patients.
Study co-senior author Leandro Cerchietti, Ph.
D.
, an associate professor of medicine in the Department of Hematology and Medical Oncology and a member of Weill Cornell Medicine's Meyer Cancer Center, helped them build and test a library
of 433 drug compounds that targeted only tumor cells.
They used a large-volume, automated platform to test the drugs
.

Next, they tested the drugs
again on T-ALL cells cultured with endothelial cell lines designed in Dr.
Rafii's lab.
They found that these tumor cells were resistant to many chemotherapy treatments, and that they became more aggressive
.
Single-cell RNA sequencing showed changes
in gene expression that affect multiple gene pathways when endothelial and cancer cells grow together.
Endothelial cells are destroyed and express genes
that promote cancer growth.
Endothelial cells extracted from T-ALL tumors expressed the same gene, suggesting that the model reproduces what happens
in vivo.

"This is a groundbreaking finding that T-ALL relies on endothelial growth factors to respond to many treatments," said Dr.
Rafii, who is also the Arthur B.
Belfer Professor of Genetic Medicine and a member of
the Meyer Cancer Center at Weill Cornell Medicine.
"When blood vessels are damaged, chemotherapy doesn't
work.
"

During the drug screening process, they found that five chemotherapy methods remained effective
despite damage to endothelial cells.
The drugs also slowed tumor growth and spread in T-ALL mice and prolonged survival in mice
.
One such drug is irinotecan, which has long been used to treat gynecological and colon cancers
.
Dr.
Inghirami noted that the drug had previously been used to treat blood cancers and was later abandoned
.
But new evidence suggests revisiting the drug
.
Changing the drug and applying the clinician's experience in managing its side effects may lead to better results
, he said.

Dr.
Inghirami, who is also a hematologist at New York-Presbyterian/Weill Cornell Medical Center, said the "Ferrari-style" platform the team developed for research could have a greater
impact than individual drug discovery.
He explained that despite promising preclinical studies, most drug candidates fail in clinical trials
.

"Because we may use a preclinical system with insufficient information to study drugs, there will be huge attrition
of personnel," he said.
It is believed that the results of drug testing on a single cell type in the laboratory accurately reflect what
is happening in the body.
”

Instead, Dr.
Inghirami recommends using the team's platform to screen drugs in increasingly complex systems, including multicellular samples, organoids, and patient-extracted mouse models
.
Drug candidates screened in this way may have a better chance of success
in clinical trials.

"This step-by-step approach could revolutionize the way we study drug candidates in the lab and lead to more successful clinical trials
," he said.