The Most Urgent Project in Colon Cancer Research: In vivo Proof of Anti-PAK1 Drugs' Effectiveness

Colon cancer is the "number 1" killer in Australia. The 1960 Nobel laureate
MacFarlane Burnet (1899-1985) in Melbourne, a great spiritual mentor of
mine during my university days in Tokyo, who inspired me to study the molecular biology
of immunological self-recognition, was among the numerous victims of colon
cancer. However, so far no effective therapeutic has been developed for
this formidable cancer as yet.

In 1989, a few years after his death, it was revealed that 50% of human colon cancers
carry the oncogenic mutant of RAS (mostly K-Ras), suggesting that abnormal activation
of this RAS is among the major causes of this cancer. Since RAS activates
the kinase PAK1, and RAS-induced malignant transformation requires this kinase,
it would be clear that at least 50% of colon cancers,
namely "RAS" colon cancer, could be treated effectively by anti-PAK1 drugs
such as Bio 30 which are available on the market inexpensively.

How about the remaining "non-RAS" colon cancers which carry no RAS mutant?
Around 1991 it was reported that more than 70% of human colon cancers carry
a loss-of -function mutation (dysfunction) of the tumor suppressor p53,
and the oncogenic RAS mutation and the dysfunction of p53 co-operate for
the malignant transformation, suggesting that p53 normally blocks the RAS-induced
malignant transformation. In other words, at least 70% of human colon cancers
including all RAS and 40% of the remaining non-RAS (=p53-deficient) colon
cancers could be treated effectively by anti-PAK1 drugs.

How about the remaining 30% of human colon cancers which carry neither RAS
nor p53 mutant? Around 1996 it was found that more than 90% of human colon
cancers carry a loss-of-function mutation of the tumor suppressor APC, and
a combination of both the oncogenic RAS mutation and the dysfunction of APC
is essential for the malignant transformation (either RAS or APC mutation
alone is insufficient to cause this cancer). In other words, APC normally
blocks the RAS-induced malignant transformation, and therefore at least 90%
of human colon cancers including all RAS and 80% of the remaining non-RAS
(=APC-deficient) colon cancers could be treated effectively by anti-PAK1 drugs.

However, so far nobody has experimentally confirmed in vivo that one of
the anti-PAK1 drugs available on the market can indeed suppress the growth
of human colon cancer, xenografts in mice or clinically. In my opinion,
that would be the most urgent project to be performed for identifying the
first effective therapeutics for colon cancers.

In 2003 Shigetoshi Kadota's group at Toyama Medical and Pharmaceutical University
in Japan reported that CAPE (caffeic acid phenethyl ester) and its analogues block
the lung metastasis of colon cancer cell line (26-L5) in mice. CAPE inactivates
the kinase PAK1 by down-regulating the GTPase RAC. However, CAPE alone has never
been clinically used, mainly due to its poor bioavailability (water-insolubility)
. Instead Bio 30, a CAPE-rich extract of NZ propolis available on the market
inexpensively, has been proven to be effective in blocking the growth of
several PAK1-dependent cancers such as pancreatic and breast cancers, NF
(neurofibromatosis) tumors, gliomas and melanomas in vivo (both xenograft
in mice and clinically), due to its high bioavailability and synergy between
CAPE and several other anti-cancer ingredients such as pinocembrin and galangin.
Thus, it would be quite reasonable to test the therapeutic effect of Bio
30 on human colon cancers in vivo, to begin with.

Besides Bio 30, Brazilian green propolis extract (GPE), which is based on ARC
(artepillin C), instead of CAPE, also inactivates PAK1 (Messerli, S. et al, 2009),
and suppresses the growth of colon cancers in vivo (Shimizu, K. et al, 2006),
although GPE is far more expensive than Bio 30. These findings altogether confirmed
that colon cancers indeed require PAK1 for their growth.