Sartorius eBook - 13

THE FUTURE OF DRUG DISCOVERY: LIVE 3D CELL ANALYSIS

for the proliferation and/or survival of these

better recapitulates how these cells appear in

tumor cells and thus represents a high-value

the body," says Timothy Spicer, Ph.D., director of

target for therapeutic development. Direct

lead identification discovery biology and HTS on

targeting of RAS has proven challenging for

Scripps Research's Florida campus and one of the

multiple reasons stemming from the biology

study's corresponding authors.

of the protein, the complexity of downstream
effector pathways and upstream regulatory
networks. Thus, significant efforts have been
directed at identifying downstream targets on
which RAS is dependent. These efforts have
proven challenging, in part due to confounding
factors such as reliance on two-dimensional
adherent monolayer cell cultures that
inadequately recapitulate the physiologic context
to which cells are exposed in vivo," write the
investigators.
"To overcome these issues, we implemented
an HTS approach using a spheroid-based
3-dimensional culture format, thought to more
closely reflect conditions experienced by cells

Confocal microscopy of the BxPC-3-KRASG12V cell line.

"Until now, most of the research to screen for

in vivo. Using isogenic cell pairs, differing in

cancer drugs has used cells that are growing flat

the status of KRAS, we identified Proscillaridin

on a plate," adds Louis Scampavia, Ph.D., director

A as a selective inhibitor of cells harboring the

of HTS chemistry and technologies at Scripps

oncogenic KRasG12V allele. Significantly, the

Research and one of the study's co-authors. "With

identification of Proscillaridin A was facilitated

these 3D spheroids, we emulate much more

by the 3D screening platform and would not

closely what's found in living tissues."

have been discovered employing standard 2D
culturing methods."
"What's important about this research is that

The spheroids are 100 to 600 μm in diameter,
equivalent to the thickness of a few sheets of
paper. In contrast to single layers of cells normally

we're able to do studies using a form of cancer

used to screen for drugs, which tend to all grow

cells that are more physiologically relevant and

at the same rate because they get the same

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| 13


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Sartorius eBook

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