VEGR and Cell Signaling

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Practical Urology: EssEntial PrinciPlEs and PracticE

Moving from Biology

humanized, meaning it has been modified to

to Targeted Therapy

resemble antibodies normally produced by

humans (as opposed to rabbits, mice, or other

mammals). This modification is what permits

The basic biology of the VHL-HIF cascade

the antibody to be used repeatedly in the same

described above is an elegant example of how

patient without the body automatically recog-

years of work by many talented investigators has

nizing it as foreign and eliminating it from cir-

shed light on the inner workings of a particular

culation. This novel, targeted agent was first

cancer. Had the story ended there, however, one

tested in a randomized phase II trial and found

might argue what the relevance is to modern

to increase the time to progression of advanced

medicine. How does this impact on health care

RCC when compared to placebo.59 It has now

and our patient’s well being? The real beauty of

been tested in a large scale phase III trial in

this story lies in the movement in the last several

combination with IFNafor men with previously

years from the “bench top” to the bedside of

untreated advanced renal cell carcinoma.60 The

patients with clear cell RCC. For several decades

combination regimen improved the progression

the management of metastatic RCC was based

free survival from 5.4 months to 10.2 months

on the use of immunotherapy including inter-

when compared to interferon alone. Based on

feron a(IFNa) and interleukin 2 (IL-2).56 These

these studies, Bevacizumab in combination with

agents produced response rates on the order of

IFNais now one of the frequently utilized thera-

only 10–20%, only a minority of which were

pies for advanced RCC.

durable complete responses. For the remainder

the responses were temporary such that the 5

The Tyrosine Kinase

and 23%.57,58 Essentially, this meant that 80–90%

year survival of metastatic RCC was between 0%

of patients with advanced RCC did not respond

Inhibitors (TKIs)

to any appreciable degree to therapy, a situation

that cried out for new and innovative agents.

An alternate approach to blocking VEGF is to

A look again at the VHL-HIF-VEGF pathway

abrogate the downstream signaling after it binds

we have described so far suggests that if one can

to its receptor (see Fig. 12.4). As we discussed,

interfere with the cascade of events, then in the-

the receptor for VEGF (as well as PDGF and

ory one ought to be able to treat clear cell RCC.

TNFa) are tyrosine kinases. When the ligand

Stated another way, if one targeted components

(VEGF) binds to the receptor (VEGFR) a

of the pathway, then the process of carcinogen-

tyrosine in the receptor is phosphorylated,

esis and tumor progression should be reversible.

allowing further downstream signaling to take

This concept of so called “Targeted Therapies,”

place via at least one of the two pathways, the

in which specific components of the tumor’s

Raf-MEK-ERK and the PI3-kinase-AKT-mTOR

biology are attacked and interrupted, forms the

pathways. Many of the members of these down-

basis for many of the therapies that have become

stream signaling cascades also rely on kinase

the standard of care for advanced clear cell RCC.

activity. It would seem logical, then, to look for

Given the connection between aberrations in

agents that can block this signaling cascade and

VHL protein function, leading to accumulation

thereby interrupt the oncogenic signaling down-

of HIF, and subsequent upregulation of VEGF, it

stream of VHL and HIF. The early attempts

was logical to explore the use of an inhibitor of

developing these tyrosine kinase inhibitors

VEGF as one of these novel approaches.

(TKIs) were relatively specific for the VEGF

Conceptually the easiest way to block the

receptors’ tyrosine kinase activity.61,62 The

action of elevated VEGF would be to directly

results were generally disappointing and these

inhibit the molecule itself (see Fig. 12.4). One

agents have largely been abandoned. In the

such approach utilizes a humanized monoclonal

course of these studies,though,it rapidly became

antibody to bind and sequester VEGF, Beva-

apparent that less specific tyrosine kinase inhib-

cizumab (Avastin, Genentech, Inc.).59 The anti-

itors, ones that could affect several different sig-

body has been designed so that each antibody

naling molecules simultaneously, were more

molecule is identical (monoclonal or originat-

effective. This is presumably due to the ability to

ing from the same cell clone). It has also been

interrupt the signaling cascade at multiple levels

simultaneously utilizing one agent. This concep-

Sorafenib is also an orally bioavailable, multi-

tual framework has resulted in the development,

targeted tyrosine kinase inhibitor, which was

testing, and now approval of several agents in

originally developed as a specific inhibitor of

this drug class. There is a rapidly expanding

Raf-1, a member of the Raf/MEK/ERK pathway

pool of potentially active drugs of this type (eq.

downstream of receptors important in the VHL/

AG-013736, GW572016, PTK787/ZK222584, plus

HIF axis (see Fig. 12.4) such as VEGFR and

others) but for the purpose of this chapter we

PDGFR and the same (in principle) to the path-

discuss the two with large scale, published phase

ways targeted by Sunitinib.71 Subsequently, stud-

three trial data confirming their clinical utility

ies showed it could also block the downstream

and which are now both approved for use in

signaling of a variety of other tyrosine kinases,

metastatic RCC (for a more in depth review of

including VEGFR, PDGFR, as well as others. As

the other agents see Lane et al.,54 Shaheen and

was the case with Sunitinib, the initial phase II

Bukowski,63 and Amato64).

studies with Sorafenib showed promise, with

Sunitinib is an orally bioavailable multitar-

substantial improvements in progression free

geted tyrosine kinase inhibitor. It has been

survival.39,72 These in turn lead to a large-scale,

shown to block the downstream signaling from

multicenter, international, randomized, pro-

several tyrosine kinase receptors important in

spective trial of 903 patients with clear cell RCC

RCC, including the receptors for VEGF and

who had failed at least one prior systemic ther-

PDGF.65,66 Phase I studies showed promising

apy.73 Patients were randomized to either oral

results in the setting of advanced RCC67 prompt-

Sorafenib versus placebo. Sorafenib was supe-

ing investigators to initiate two phase II studies

rior to placebo with respect to progression free

in patients who had failed prior systemic

survival and it was generally well tolerated,

cytokine therapy followed by a large, prospec-

though there were rare cases of significant

tive, randomized phase III trial in patients who

hypertension and cardiac ischemia. As with

had not received prior systemic therapy.68–70 In

Sunitinib, the salient point is that the success of

the phase II trials, both designed to test the effi-

this oral, small molecule agent lies in its devel-

cacy of Sunitinib in the setting of patients with

opment to specifically target a pathway involved

metastatic RCC who had failed prior systemic

in the disease.

cytokine therapy (with either interferon or

interleukin-2) the partial response rates were

Targeting mTOR

34–40% and the median time to progression was

8.3–8.7 months.69,70 Based on these promising

results, a large scale, international, multicenter,

As we have discussed,aberrations inVHL under-

prospective, randomized, phase III trial was

lies the process of carcinogenesis in clear cell

completed that enrolled 750 patients with clear

RCC, which in turn leads to accumulation and

cell RCC who had not received prior systemic

build up of HIFa in RCC cells. Conceptually,

therapy.68 Patients were randomized to either

another way to block the buildup of HIFa in the

Sunitinib or IFNa with the primary endpoint of

cell is to interrupt its initial or starting levels.

the trial being progression free survival (PFS).

There are a number of important pathways that

The partial response rate for Sunitinib was 31%,

impact on the expression of HIFa, but one of the

significantly better than the 6% for patients ran-

most important is the Akt/mTOR pathway.

domized to IFNa. The median progression free

Signaling from the mTOR pathway leads to

survival was significantly better in patients who

increased expression of HIFa mRNA and then

received Sunitinib (11 months) compared to

to increased starting levels of the protein. In

5 months for those in the IFNa arm. Toxicity

RCC, buildup of HIFa leads to increased signal-

was generally manageable. These results dem-

ing along the Akt-mTOR pathway, which leads

onstrated the superiority of the oral TKI

to upregulation and increased levels of HIFa,

Sunitinib over IFNa in the front line setting for

which cannot be targeted for degradation by

advanced RCC. The critical point to note is the

association with VHL since it is abnormal in

development and testing of this tyrosine kinase

clear cell RCC. This vicious cycle, or positive

inhibitor flowed directly from an understanding

feedback loop, as reviewed already, is thought to

of the molecular biology that underlies the dis-

be important in RCC. Strategies to interrupt this

ease it is treating (advanced RCC).

cycle presumably would be effective in treating