PI3K inhibitors - a review

[Guest guest]

The cover story (below) of this week's issue of Chemical and

Engineering News has a very nice (and 'free') review of the history

and status of the development of the many different PI3K inhibitors

as therapeutic agents for cancers in general. Although the review is

technical in nature, it is fairly easy to read.

One of the SNIPs (below) from the review discusses CAL-101 (i.e.

" Calistoga's delta-isoform inhibitor " ), pointing out the clinical

significance for CLL therapy of PI3K-delta only being expressed in

" white blood cells " .

A general conclusion of the review is that use of PI3K inhibitors for

therapy of cancers may require combination with other (targeted)

therapies, indicating that requirement is likely of greater need in

more aggressive cancers.

Although not discussed, a related implication is that mono-therapy

with PI3K inhibitors alone may be sufficiently effective in

untreated, low-risk, slow-progressing cancers. Because most initial

cancer clinical trials involve patients who are refractory with

aggressive disease, little/no clinical data exists yet for use of

PI3K inhibitors for untreated patients who slowly-progressed to a

point of needing treatment, a situation that is more common in CLL

than for most other cancers. " Only keeping tumors from growing and

not killing them " may be sufficient for some of these CLL patients.

REVIEW PAPER:

" PI3K At The Clinical Crossroads "

After a frenzy to develop better and more selective PI3K inhibitors,

companies now must figure out how to use them in cancer patients

CHEMICAL AND ENGINEERING NEWS, April 11, 2011 Volume 89, Number 15; pp. 15 - 19

FULL-TEXT FREE at: http://pubs.acs.org/cen/coverstory/89/8915cover.html

---- beginning of quotes -------

SNIP......

The Oncothyreon and Genentech drugs inhibit most members of the PI3K

family, but researchers have more recently become interested in

compounds that block a single isoform of PI3K. The argument for this

highly targeted approach is that such compounds will be better

equipped to work in combination with other therapies. " You want to

get maximum efficacy hitting that enzyme, while minimizing off-target

activity in order to increase your chances of success, " Intellikine's

says.

Although companies have been working on the approach for several

years, new positive data for Calistoga's delta-isoform inhibitor has

generated excitement that the highly targeted drugs could be

effective in certain cancers.

Calistoga chose to focus on PI3K because, unlike the more prevalent

alpha- and beta-isoforms, it is only expressed in white blood cells.

Since the delta-isoform plays a role in modifying lymphocyte

function, the company was initially focused on finding drugs that

might have an impact on inflammatory diseases. Then Calistoga

scientists considered that the compounds might also be useful in

blood cancers, which in essence are " inflammation gone amok, " says

Langdon L. , the firm's vice president of R & D.

In December, Calistoga reported data from two Phase I trials testing

its lead compound, CAL101, as both a single agent and in combination

with two already approved therapies, Treanda and Rituxan, in patients

with chronic lymphocytic leukemia. In the single-agent trial,

patients who didn't respond to at least five other medicines all saw

their tumors shrink. The majority also saw a reduction in lymph node

swelling of more than 50%.

" Our preliminary data suggest that diseases with the most

inflammatory characteristics are the ones that respond best to

treatment, " says. " In some ways, these are the patients that

on conventional therapy would do the worst. "

Calistoga's success in the clinic, not to mention its big-ticket

acquisition by Gilead, has bolstered other small companies that are

developing isoform-selective compounds.

SNIP.......

But it has become clear that a PI3K inhibitor used on its own is 'in

most cases' only keeping tumors from growing, not killing them.

SNIP..........

While companies argue the pros and cons of broad versus selective

PI3K inhibitors, Genentech sees merit in having an array of

therapeutic options. " There are going to be aggressive diseases where

you need to clamp down on the pathway very hard and quickly, and

other indications where you'll want a more selective and safe type of

inhibitor, " Olivero says.

SNIP.......

" My feeling is that PI3 kinase inhibitors will be a very important

part of targeted therapy moving forward, " Engelman adds. " This

pathway is very important for the survival of cancer cells, but we're

still learning how to use these drugs appropriately. "

-----end of quotes --------

Al Janski

[Guest guest]

Al,

I wonder if some readers will be confused by your snippets.

Regarding CAL-101 you say " the majority also saw a reduction

in lymph node swelling of more than 50% " .

Three snippets later you say " But it has become clear that a

PI3K inhibitor used on its own is 'in most cases' only

keeping tumors from growing, not killing them. "

The full text paper makes clear that CAL-101 is a sub-

species of PI3K inhibitor, an omega isoform (if my Greek is

right), and has shown tumor efficacy to date. Your general

statement about PI3K inhibitors is true, but potentially

misleading about CAL-101. Long-term caveats aside and

granting that you may have been referring to CAL-101 by

putting " in most cases " in quotes.

Mark

[Guest guest]

At 03:17 PM 4/16/2011, Mark " mschaeffer3 " wrote:

>Regarding CAL-101 you say " the majority also saw a reduction in

>lymph node swelling of more than 50% " . Three snippets later you say

> " But it has become clear that a PI3K inhibitor used on its own is

>'in most cases' only keeping tumors from growing, not killing them. "

In those two SNIPs from the review, I actually intended to

contrast what the review indicated for efficacy (a

" success " ) in a " single-agent trial " of a specific PI3K-

delta inhibitor (i.e. CAL-101) vs. what the review concluded

overall for PI3K inhibitors in general. And, yes, I

highlighted " in most cases " , because I assumed the author

used that phrase in recognition of the CAL-101 reference

being an exception to that stated generality.

Although the review described the unique situation of

CAL-101/CLL, i.e. using a delta-isoform inhibitor (i.e.

CAL-101) to selectively treat cancer cells (i.e. CLL)

expressing only the delta-isoform of PI3K, I think the

author could have given more discussion to it.

btw, the SNIP in my original post should have read

" Calistoga chose to focus on PI3K-delta...... " , not

" Calistoga chose to focus on PI3K...... " . Because the

Greek symbols did not transcribe into my plain text email, I

had to add them back in their 'word' form and missed (at

least) that " delta " .

Al Janski