In this interview, a representative from the clinical
development team of Calithera Biosciences
discusses the potential impact of a novel drug
combination undergoing study in a pivotal global
randomized Phase 2 trial in renal cell carcinoma.
Sam Whiting, MD, PhD, is Senior Vice
President of Clinical Development. The new
drug in development is teleglenastat (CB-839). One of the goals
in the study is to demonstrate how targeting tumor metabolism
pathways may take advantage of cancer-specific nutrient dependencies
to block cancer growth. The interview was conducted
by Robert A. Figlin, MD, Editor-in-Chief of the Kidney
Cancer Journal.
Dr Figlin: Let’s begin by examining some topics related to
tumor metabolism and biology and how various factors
could play a role in promoting cell growth and proliferation.
Please describe the importance of metabolic pathways
in kidney cancer and how your work relates to such
mechanisms.
Dr Whiting: Metabolism is altered in cancer cells and a lot
of oncologists know this from their training, that glucose
metabolism in cancer typically is shunted toward production
of lactic acid which is secreted from cells and
shunted away from entry into the tricarboxylic acid
(TCA) cycle, or Kreb’s cycle. Called the Warburg Effect,
this metabolic phenomenon has been known for almost
a century. The problem has been how best to target the
abnormal metabolism in tumor cells.
The unique thing about inhibition of glutaminase as
targeted by teleglenastat (CB-839) is that alterations in
glucose metabolism in tumor cells are linked to alterations
in glutamine metabolism. And, in particular, as
cells use less glucose to drive the TCA cycle and other
biosynthetic pathways, they use more glutamine. What
Calithera did was to develop an inhibitor of glutamine
metabolism that would specifically block the conversion
of glutamine to glutamate in the cancer cell and “starve”
cancer cells of this necessary amino acid. This process is
fundamentally important to cancer cells because of their
altered metabolism.
So glutamine biology is important to cancer cells because
of their inherent difference from healthy cells and
that allows telaglenastat to have more of a metabolic impact
on tumor cells compared to healthy cells, which is
an important characteristic of the drug.
22 Kidney Cancer Journal
Dr Figlin: Help us understand some of the preclinical and
Phase 1 results that have led to the CANTATA trial, which
is looking at a combination with a tyrosine kinase inhibitor.
Dr Whiting: The first preclinical work that we performed
with telaglenastat was biochemical studies in the laboratory
to show that the drug hit its target in cancer cells,
which is an enzyme called glutaminase, and hitting that
target in cancer cells did what was expected, that is, shutting
down glutamine metabolism in the cancer cell. We
demonstrated in a large number of cancer cell lines, representing
many different types of cancer, that telaglenastat
shut down glutamine metabolism in the cancer cell.
We also were able to track the repercussions of that blockade
in a cancer cell, showing that downstream products
of glutamine metabolism that cancer cells were relying
upon were decreased or blocked as well. Those included
molecules used for DNA synthesis, fatty acid synthesis,
and to protect cancer cells from oxidative stress. All of
these, we were able to show in the lab, were inhibited by
telaglenastat but, importantly, it didn’t have the same effect
in normal tissues.
Dr Figlin: Can you differentiate aspects of tumor and normal
cell metabolism that need to be considered? What
effect does the drug have in these settings?
Dr Whiting: The reason for the drug not having the same
effect on normal cells is that cancer cells, to put it a crude
way, can be addicted to glutamine to feed pathways for
which healthy cells predominantly use glucose. We had
this metabolic inhibitory effect in cancer cells and we
showed that the effect was not nearly as strong in healthy
cells.
Then we went into tumor models in animals and
showed that we can inhibit the growth of tumors in animals
just as we could kill cancer cells in the lab. And
again, looking in the animal, the impact of telaglenastat
was predominantly seen in the cancer and not in healthy
tissues. This took a few years of diligent work and, ultimately,
led to the initial Phase 1 program where telaglenastat
was tested in patients with cancer. That was a very
thorough clinical program that looked at the drug in a
significant number of patients with a variety of cancer
types.
Dr Figlin: What led you to focus more specifically on RCC?
INTERVIEW
A Novel Combination Therapy Takes an Innovative
Approach by Targeting a Key Metabolic Pathway
to Block RCC Growth