Index for Glioblastoma

Index for Glioblastoma in Cracking Cancer Toolkit

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Glioblastoma 52 appearances in text

p. 13

• Ben Williams—Surviving Glioblastoma:
Ben Williams was a psychology professor
at the University of San Diego when he
was diagnosed with terminal brain cancer
(glioblastoma), a uniformly fatal incurable
disease. This was before the Internet
and PubMed, so Mr. Williams accessed
the University medical library in person,
spent hours on research, and devised
his own cocktail of repurposed drugs.
Many were purchased over the counter
by driving across the border to Mexico.

Surviving “Terminal” Cancer: Clinical Trials,
Drug Cocktails and Other Treatments Your
Oncologist Won’t Tell You About (Fairview
Press, 2002).


METRICS and the COC Protocol for
Cancer Doubles Survival in Glioblastoma
In 2019, Dr. Samir Gupt Agarwal et al. of
COC proposed their protocol for cancer, which
involves use of the four of the repurposed drugs
mentioned above: metformin, atorvastatin,
mebendazole, and doxycycline. Preliminary
data was presented in 2019 for 95 glioblastoma
patients in their clinical trial (METRICS study
NCT02201381). The preliminary data showed
the COC protocol nearly doubled the survival
time of glioblastoma patients from 14 to 28
months and doubled the number of patients
surviving to the 2-year mark. (34)

p. 28

40) Kast, Richard E., et al. “Glioblastoma-synthesized
G-CSF and GM-CSF contribute to growth and immunosuppression:
Potential therapeutic benefit from
dapsone, fenofibrate, and ribavirin.” Tumor Biology
39.5 (2017).

p 43
Chinese skullcap was also effective as an
anti-cancer agent in lung cancer, acute myeloid
leukemia (AML), and glioblastoma cell models.
(27–33) Baicalin (Chinese skullcap root)
penetrates into the CNS, according to Stephen
Harrod Buhner, and baicalin is concentrated in
the brain, striatum, thalamus, and hippocampus.


p 51

DCA Synergy with Anti-VEGF Antibody (Avastin)

In 2013, Dr. Krishan Kumar et al. used
an in vivo glioblastoma xenograft model to
study drug resistance to the anti-angiogenic
drug bevacizumab, an anti-VEGF antibody
(VEGF=vascular endothelial growth factor).
The two drugs, bevacizumab and DCA used
together “dramatically blocked tumor growth”
compared to either drug alone, making it a
potent anti-cancer strategy. (27)

p 56.

Dr. Thomas Seyfried writes (2015):

Our data indicate that metformin enhancement
of DCA cytotoxicity is dependent
on complex I inhibition. Particularly, that
complex I inhibition cooperates with DCA induction
of glucose oxidation [OXPHOS]
to enhance cytotoxic oxidative stress in
VM-M3 GBM (glioblastoma) cells. (68)

p. 57
DCA for Glioblastoma Stem Cells

Glioblastoma cells and their stem cells are
highly glycolytic and a good target for the glycolysis
inhibitor DCA, which easily crosses the blood-brain barrier (BBB). In 2010, Dr. E. D.
Michelakis et al. studied the effect of DCA on
glioblastoma cells (GBM) freshly isolated from
49 patients. In addition, 5 patients with GBM
were treated with oral DCA over 15 months,
together with the oral methylator temozolomide,
with promising results. Both glioblastoma
bulk tumor cells as well as (CD 133+)
stem cells showed an excellent response to the
DCA. They conclude:

DCA treatment was associated in some
GBM patients with prolonged radiologic
stabilization or tumor regression and, in
general, displayed an overall good safety
profile. This early, first-in-human report
provides a rationale for extended studies
with this generic small molecule in patients
with GBM. (92)

In 2012, Dr. Marie Morfouace et al. found
that DCA in combination with etoposide or
radiation potentiated apoptosis in glioblastoma
CSCs in vitro and reduced proliferation in
vivo, via a Bax pathway. Bax is a pro-apoptotic
protein and member of the BCL-2 family. (93)

Fatal Outcome Combining
DCA and Artesunate
In 2016, Dr. Martin Uhl et al. published a
case report of fatal outcome using the combination
of DCA and Artesunate in a Glioblastoma
patient who experienced both fatal liver failure
and bone marrow toxicity after combined use
of DCA and Artesunate. Therefore, it would be
prudent to use extreme caution or avoid this
combination. The two agents have different
mechanisms of action. DCA is a glycolysis inhibitor,
shifting metabolism back to mitochondrial
OXPHOS, which creates increased reactive oxygen
species (ROS). Artesunate also creates ROS
by reacting with Iron in lysosomes. This case
highlights the importance of using a knowledgeable
physician who can monitor adverse
side effects and serial blood labs such as liver
function tests (LFTs) during treatment for early
detection of adverse events. For more on this,
see chapter 21 on artesunate. (142)

p. 199
Metformin Synergy with Dichloroacetate (DCA)

In 2017, Dr. Ward studied the synergistic
effects of metformin with the glycolysis inhibitor,
dichloroacetate, using the in vitro glioblastoma
model. Dr. Ward found increased
superoxide production by combining metformin
with glycolysis inhibitor DCA, which
shunts electron flow into the mitochondrial
ETC. The inhibition of complex I of the ETC in
the mitochondria by metformin causes superoxide
ROS which overwhelms the anti-oxidant
defense of the cancer cell, leading to mitochondrial-
induced apoptosis. Dr. Ward writes:
These data suggest that complex I inhibition
cooperates with DCA activation of
oxidative glucose metabolism to promote
catastrophic oxidative stress in VM-M3
glioblastoma cells. (52)


p 245
On April 16th, 2016, I attended the 14th
Annual International Integrative Oncology
Conference in San Diego, California. At the
meeting, Dr. Nooshin Darvish presented five
case reports of glioblastoma multiforme
treated over ten years at her Holistique Clinic in
Bellevue, Washington. All five patients underwent
surgical biopsy of the tumor mass, and
all samples stained positive for the spirochete
parasite, Borrelia, the organism found in Lyme
disease. (1)
In all cases, the patient’s tumor regressed
upon treatment for parasitic disease and progressed
when treatments were halted

In 2013, Dr. Anja Wieland et al. found
niclosamide effective against glioblastoma
cell lines, a deadly form of brain cancer. This
explains the dramatic improvements in five
patients with glioblastoma multiforme presented
by Dr. Nooshin Darvish et al. when
treated with antiparasitic drugs, as described
above. (51) Niclosamide was patented in 2012
for treatment of metastatic cancer.

p 323
30) Bai, Ren-Yuan, et al. “Antiparasitic mebendazole
shows survival benefit in 2 preclinical models of glioblastoma
multiforme.” Neuro-oncology 13.9 (2011):

p 356

6) Lefranc, Florence, et al. “Cimetidine, an unexpected
anti-tumor agent, and its potential for the treatment
of glioblastoma.” International journal of oncology
28.5 (2006): 1021-1030.

p 366
Case Report: Beta Glucans for Glioblastoma

In 2016, Dr. John Berg declared a “paradigm
shift” in glioblastoma treatment, proposing a
combination of repurposed drugs and supplements.
This includes both cimetidine and beta
glucans, two of the immunomodulatory agents
we have already discussed. Also included in his
drug cocktail is fenofibrate, discussed in chapter
37. (98)

98) Berg, John. “A Paradigm Shift in Glioblastoma
Treatment and Research: A Multi-mechanistic, Multiagent
Approach to Target Glioblastoma Multiforme.”
Journal of Advanced Medical Sciences and Applied
Technologies 2.4 (2016): 323-326.

p 408

Glioblastoma Case Report
Autophagy Inhibitor Combination
In 2014, Dr. Jean Levy et al. published a case
report of autophagy inhibition in a patient with
brainstem ganglioglioma successfully treated
with vemurafenib (inhibitor of BRAF kinase)
and vinblastine (vinca alkaloid microtubule
inhibitor) for one year, until tumor recurrence
refractory to further drug or radiation treatment.
Quite dramatically, the patient enjoyed
a sudden improvement when chloroquine was
added to the vemurafenib drug. Dr. Levy et al.
The patient had rapid improvement in
the neurologic deficits accompanied by
decreased inflammatory signal and stabilization
of intracranial CNS [central nervous
system] lesions. For a period of time, this
patient had to stop taking vemurafenib but
remained on CQ [chloroquine]. This too
led to increased tumor growth and disease
progression. Most importantly, when she
was again treated with the combination of
vemurafenib plus CQ, her tumor regressed,
neurological deficits were again reduced
and continued tumor control was maintained
for more than two years … autophagy
inhibition with CQ is not only capable
of making an active drug better, it can
actually overcome the acquired resistance
that occurs when a kinase inhibitor stops
working. (44–46)

p 409
Chloroquine for Glioblastoma

Clinical Study: Dr. Sotelo
As of 2019, there were 21 clinical trials
evaluating chloroquine for cancer treatment,
and 66 for hydroxychloroquine. Perhaps the
most promising outcome so far is the 2006
randomized clinical trial by Dr. Julio Sotelo
et al. in Mexico, adding oral chloroquine (150
mg/day) to conventional treatment (chemo-
radiation) in thirty glioblastoma patients
over 12 months. Conventional chemotherapy
with temozolomide was given. (47–48)
47) Sotelo, Julio, Eduardo Briceno, and Miguel Angel
López-González. “Adding chloroquine to conventional
treatment for glioblastoma multiforme: a randomized,
double-blind, placebo-controlled trial.” Annals
of internal medicine 144.5 (2006): 337-343.
48) Weyerhäuser, Patrick, Sven R. Kantelhardt, and Ella
L. Kim. “Re-purposing chloroquine for glioblastoma:potential merits and confounding variables.” Frontiers
in oncology 8 (2018): 335.

The hydroxychloroquine treated group had two
patients still in remission at 24 months, while
the control group had no patients surviving
past 22 months. Median survival for the chloroquine-
treated group was double that of the
control patients. Dr. Sotelo and his colleagues
Median survival after surgery was 24
months for chloroquine-treated patients
and 11 months for controls. (47–49)
I thought this was very impressive.

p 439
Thymoquinone Autophagy Inhibitor
In 2013, Dr. Ira Racoma et al. studied the
effect of thymoquinone (TQ) in a glioblastoma
cell model, finding induction of apoptosis in
a caspase-independent manner (meaning the
mechanism was related to lysosomal disruption
and not mitochondrial apoptosis):

17) Racoma, Ira O., et al. “Thymoquinone inhibits autophagy
and induces cathepsin-mediated, caspase-independent
cell death in glioblastoma cells.” PLoS One
8.9 (2013).

p 425
Loratadine is a cationic amphiphilic drug
(CAD), which enters the acidic lysosome, where
once protonated, it is trapped and accumulates
a thousand fold. As one can imagine, this
interrupts lysosomal function, and serves as an
autophagy inhibitor. (56)

p 427
CADs for Glioblastoma

In 2019, Dr. Vadim Le Joncour et al. studied
the beneficial effect of clemastine (CAD) for
glioblastoma, writing that CAD drugs should
be included as adjuvant therapy to the standard
of care. Clemastine is an antihistamine similar
to loratadine:

Bearing in mind the chemo‐resistant nature
of infiltrating gliomas and the poor delivery
of conventional drugs due to the BBB
[Blood Brain Barrier], the repurposing of
antihistamines and other CADs to trigger
the LMP [lysosome membrane permeability]
in invasive neoplasms should be
considered as an adjuvant therapy to the
standard of care, i.e. the surgical resection
of the primary tumour and conventional
radio‐ and chemotherapies. (62)

p 464
Dr. Richard Kast and Itraconazole as Hh Inhibitor

Dr. Richard Kast et al., write in Oncotarget
(2017) that itraconazole is useful in glioblastoma
as a hedgehog inhibitor, which decreases
the cell proliferation rate and enhances apoptosis
in glioblastoma cell lines:
The primary mode of anti-cancer action is
inhibition of Hh [Hedgehog] signaling …
Itraconazole inhibits release of Gli1 thus
keeping it sequestered in the cytoplasm …
In preclinical studies itraconazole inhibition
of Hh signaling inhibited growth of breast
cancer, melanoma, and endometrial cancer.(

42) Kast, Richard E., et al. “Blocking epithelial-to-mesenchymal
transition in glioblastoma with a sextet of
repurposed drugs: the EIS regimen.” Oncotarget 8.37
(2017): 60727.

Published on by Jeffrey Dach MD

About Jeffrey Dach MD

Medical Director of TrueMedMD, a Clinic in Davie Florida specializing in Bioidentical Hormones and Natural thyroid. Office address 7450 Griffin Road Suite 190, Davie, Florida 33314 telephone 954-792-4663