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Velcade: the Magic Bullet for Cancer?
A prostate cancer patient’s overview of an exciting new
cancer drug in development and trial .
September 2003
While Bill Aishman may have
been excited about Velcade back in 2003, it hasn't lived up to any promise
as far as HRPC is concerned . A 2007 (4 years after Bill's analysis)
paper (a) illustrates this. This phase II clinical trial of taxotere and
bortezomib (Velcade) with metastatic HRPC patients who were chemo-naive only
resulted in a PSA RR (≥50% drop in PSA) in 25% of the patients and a median
duration of response of 8 months. Furthermore, the
median progression-free and overall survival times for the entire group were
4.1 months and 13.8 months, respectively. The dose of taxotere was
30mg/m2 and velcade was 1.6mg/m2 on days 1, 8, and 15 of a 28 day cycle.
There were 60 patients. This result is disappointing in that this
combination does not result in any real improvement over just taxotere alone
(and for PSA RR it is worse.) It might be possible that a different
schedule would produce better results.
(a)
Hainsworth JD, Meluch AA, Spigel DR,
Barton J, Simons L, Meng C, Gould B, Greco FA, Weekly docetaxel and
bortezomib as first-line treatment for patients with hormone-refractory
prostate cancer: a Minnie Pearl Cancer Research Network phase II trial, Clin
Genitourin Cancer. 2007 Mar;5(4):278-83.
Author: Howard Hansen 31 July 2007.
INTRODUCTION
After 6+ years of treating prostate cancer, my disease is
out of control. During these 6+ years, the multitude of treatments
(including 3+ years of nine different chemotherapeutic agents and protocols)
have compromised my bone marrow to the extent that I must currently skip or
delay any treatment until my bone marrow slowly recovers from the last
treatment. Meanwhile, my disease is out of control. This late-stage medical
management of our disease is an art---not a science. We are trying to
balance the acceptable toxicity of treatments vs. progression of the
disease.
If our life-system has deteriorated resulting from the
disease or treatment toxicity to the extent that it denies conventional
drugs or treatments available, we must seek some experimental agent to
prolong survival. But, this search can be very frustrating as there are
thousands of new agents in various stages of development; finding and
analyzing even a small matrix of the drugs that might be applicable to your
situation is next to impossible. And, as discussed in
http://www.hormonerefractorypca.org/clinicaltrialseditorial.htm,
even when we can qualify for a trial, 85% of patients entering trials
state their reasons for entering was the expectation of therapeutic value;
but, only 5% of clinical trial participants will benefit there from.
Moreover, it takes 10-15 years on average for an experimental drug to travel
from the lab to patients; only five in 5,000 compounds that enter
pre-clinical testing make it to human testing; only one in five drugs tested
in humans is approved. Not only are the probabilities of finding and
qualifying for a new agent trial overwhelmingly against us, the probability
that we will benefit there from is infinitesimal.
Therefore, unless your disease is low-grade and under
control at a modest progression level, I am not an advocate of entering
experimental cancer agent trials unless one portion of the trial includes an
agent in combination that has a proven therapeutic value as a stand-alone
therapy (i.e., a combination of a chemotherapy agent + a new agent; but the
expected results from the trial should exceed the known agent results as it
stands alone in treatment).
However, notwithstanding the overwhelming odds against me, I
am seeking any port in a storm given that I am denied any treatment due to
bone marrow problems. With the goal of finding an experimental drug and at
the suggestion of a leading PCa medical oncologist I am excited about a new
drug early in the development process that might be the Magic Bullet.
I realize there are hundreds of drugs in development, but this one has moved
rapidly from lab/in vitro to human testing. If you will study this
specific drug, I think you will agree that this is an exciting time for the
identification of specific molecular targets, cancer therapeutics, and
defined antitumor targets. PS-341 (Velcade) can be a breakthrough in
targeting cancer cell reproduction processes, inhibiting the same, and
resulting in cancer cell death allegedly without harming healthy cells and
without undue side-effects. Moreover, PS-341 is reversible; as soon as the
drug is stopped, normal cell replication resumes.
Understanding the mechanism/objective of this drug is
complex for a layman/patient because it involves details of cell biology.
Below I have tried to understand the mechanisms of the drug, express my
understanding in layman/patient language, and discuss why I intend to
attempt some semblance of compassionate use of the drug, since I obviously
do not qualify for any trial due to my multiple treatment sequencing.
THE DRUG......Bortezomib = PS-341 =
Velcade = a proteasome inhibitor.
...What the hell are the proteasomes and why
do they need inhibiting? The proteasomes are enzymes that are critical to an
incredible multitude of cellular processes and pathways including: cell
cycle, cell growth and differentiation, apoptosis (cell death), signal
transduction, DNA repair, regulation of transcription and DNA replication,
antigen presentation, angiogenesis (creation of new blood vessels to feed
the cell), immune responses, and many more processes in the life cycle of
each cell.
The proteasome plays a critical role in each cell via a
programmed sequence degrading numerous protein substrates that regulate both
the cell cycle and prosurvival pathways. My interpretation of the function
of the proteasomes: each cell is constantly replenishing itself by
discarding multiple substrates of proteins and providing the pathways for
their replacements. In a cancer cell, inhibition of this substrate
degradation/replication results in cell death; without them, the cell can
not replicate itself. Inhibition of the proteasome enzymes blocks all the
proteolytic (decomposition of protein) action required by the cell to
replicate itself. Thus, inhibition thereof clogs the cell with garbage,
prevents replenishment of protein substrates and cell replication; result =
cell death. And, proteasome inhibitors are allegedly selectively
cytotoxic to cancer cells and do not affect healthy cells.
PS-341 is an antineoplastic (prevents growth of cells) agent
and the first proteasome inhibitor to have progressed to clinical trials and
has exceedingly high affinity, specificity, and selectivity for catalytic
activity of the proteasome. And thus, it induces apoptosis (death) in a wide
variety of cancer cell lines, but has few toxic effects on normal cells. In
addition, it has considerable efficacy as a single agent against human tumor
xenographs and cultures of multiple cancer types, including prostate
cancer.
Equally as exciting, PS-341 markedly enhances the apoptotic
(cell death) effects of irinotecan, Gemzar, Adriamycin, the taxanes, and
radiation therapies. The ability of PS-341 to directly and specifically
cause death to cancer cells as a single agent and additionally
synergistically enhance chemo agents without undue side-effects generates
considerable excitement for me and inducement to try to obtain the drug as I
approach late-stage terminal disease status. While the etiology of our
disease is still in the dark ages, I think (hope) these molecular
targeted drugs can quickly become our Magic Bullet.
(1, 2, 3, 4)
TRIAL REPORT SUMMARIES RE PS-341/VELCADE----
(Note: since Velcade is in dosing trials, my analysis
laboriously details dose levels and side-effects.)
Velcade was developed by Millennium Pharmaceuticals, Inc.,
Cambridge, MA and the early clinical work was done by the company and
Logothetis CJ et al. at MD Anderson.
In 1999 Logothetis CJ found in vitro and
animal in vivo experiments that the ubiquitin (a protein found in all
cells)-proteasome pathway to be critical for the deregulation of many
intracellular proteins including those which control cell cycle regulation;
early dose limiting toxicity (DLT) was determined to be 0.8 mg/m2 2X/week
for 4 weeks; then 2 weeks off. (5) Aghajanian C et al. found
that PS-341 is a potent and reversible inhibitor of the proteasome, which is
the final degradative enzyme involved in an important catabolic pathway for
many intracellular regulatory proteins; the antineoplastic (preventing
development of cells) effect of the drug may involve several distinct
mechanisms including inhibition of cell growth signaling pathways, induction
of apoptosis; 21 heavily pre-treated patients were enrolled in a trial of
escalating doses from 0.13 to 1.08 mg/m2; including 3 prostate cancer
patients; no drug related toxicities were reported. Logothetis CJ et al.
conducted a trial of 19 androgen independent prostate cancer patients
@ 0.13 to 1.60 mg/m2, 4/6 weeks; one hour after IV proteasome inhibition was
achieved and no toxicity. (7)
Logothetis CJ et al. continued with a study of 41
patients with metastatic AIPCa; NFkB (a gene array; a critical mediator of
immune and inflammatory responses) is implicated in the progression of PCa
in bone and resistance to therapy; PS-341 inhibits NFkB activation; data
indicate a PSA slope decline on a dose dependent basis; weekly PS-341
may be active in PCa and its action might be mediated through the
inhibition of NFkB. (8) The Logothetis group found that in
vitro, PS-341 exhibits significant anti-tumoral activity when combined
with certain conventional DNA damaging chemotherapeutic agents used in the
treatment of advanced prostate cancer (Adriamycin,
VP-16, Gemzar)--- "Strikingly, however, combined
treatment with PS-341 and paclitaxel (Taxol) resulted in lower
levels of apoptosis than were observed in cells treated with either agent
alone."
Adams J (Millennium Pharmaceuticals, Inc.) states that 26S proteasome
regulates protein turnover in eukaryotic (a cell containing a membrane-bound
nucleus with chromosomes of DNA, RNA, and proteins) cells related to the
cell cycle, tumor growth, and survival which are governed by a large
repertoire of intercellular proteins that are regulated by the ubiquitin-mediated
proteasome degradative pathway; PS-341 is a potent, selective inhibitor of
the proteasome; because proteasome inhibition with PS-341 results in potent
antitumor activity in vitro , PS-341 may offer a promising new
approach to treating otherwise fatal malignancies. (10) Adams J
continued in another report that PS-341 is a small molecule that is a potent
and selective inhibitor of the proteasome; in vitro and mouse
xenograph studies PS-341 has shown anti-tumor activity in a variety of tumor
types, including prostate cancer. (11) Shah MH et al. found
that PS-341 may increase a progression free survival in metastatic
neuroendocrine tumors and it has a tolerable toxicity profile, but patients
developing nausea on PS-341 should be evaluated carefully given a possible
side-effect of ileus (obstruction of the bowel) and caution should be used
combining PS-341 with chemotherapeutic agents with similar
gastrointestinal toxicity. (12)
Thomas JP et al. report findings that the ubiquitin (a protein found
in all cells)/proteasome pathway is the mechanism by which a number of
short-lived proteins involved in DNA repair, cell cycle and apoptosis are
degraded and preclinical studies have shown enhanced cell killing when
PS-341 is added to a number of cytotoxic chemotherapeutic agents including
topoisomerase I and II inhibitors, DNA damaging agents and tubulin
inhibitors; PS-341 single agent trials have shown activity in prostate
cancer, as well as other cancer types; this Q21 trial adds
Adriamycin @ 15-20 mg/m2 on D1 & 8 after PS-341 + PS-341 @ 1.0-1.3
mg/m2 IV bolus on D 1, 4, 8, 11; toxicities: fatigue, rash, nausea,
anorexia, thrombocytopenia (low platelets), and exacerbation of pre-existing
neuropathic pain. (13) Iqbal S et al. report a study of PS-341 @
0.5-1.3 mg/m2 2X/week (4/6) + 5-FU @ 500 mg/m2/LV @ 20 mg/m2
weekly in 12 patients (11 colorectoral, 1 esophageal); 6/10 = stable
disease, 3/10 decrease in CEA, 1/10 partial response, 3/10 = progressing
disease; toxicities: diarrhea, dehydration, abdominal pain and cramping, no
neuropathy; MTD = 1.0 mg/m2. (14)
Ryan DP et al. reported a study of murine xenograph models of
pancreatic cancer resulted in complete tumor regression; in a 12 patient Q21
study of PS-341 @ 1.0-1.3 mg/m2 IV bolus on D 1, 4, 8, 11 + Gemzar
@ 500, 800, & 1000 mg/m2 on D 1 & 8; early results indicate MTD
of PS-341 @ 1.0 mg/m2 and Gemzar @ 1000 mg/m2. (15) Richardson PG and
a large group report a cohort of 200 heavily pre-treated multiple myeloma
patients in a Q21 study of PS-341 @ 1.3 mg/m2 by IV push on D 1, 4, 8, & 11;
85% either responded or stabilized after 2 cycles; complete responses have
been observed; PS-341 presents a new treatment paradigm targeting the
tumor cell in its microenvironment to overcome drug resistance.
(16) Orlowski RZ et al. studied single agent PS-341 in 27 patients with
refactory hematological malignancies; PS-341 @ 0.40, 1.04, 1.20, or 1.38
mg/m2 2X/week (4/6); MTD was 1.04 mg/m2, but patients have to be
monitored for electrolyte abnormalities and late toxicities; PS-341 showed
activity against refactory multiple myeloma and possible non-Hodgkin’s
lymphoma; toxicities: thrombocytopenia (low platelets), hyponatremia (low
circulating blood sodium ions), hypokalemia (low circulating blood potassium
ions), fatigue, malaise. (17)
Aghajanian C et al. designed a
study with the purpose of evaluating toxicity and pharmacodynamic behavior
of PS-341; 43 heavily pre-treated advanced solid tumor malignancy patients
were treated with 89 cycles of PS-341 @
0.13 to 1.56 mg/m2; one major response in a patient with refactory NSCLC;
MTD = 1.56; toxicities: diarrhea, sensory neurotoxicity, fatigue, fever,
anorexia, nausea, vomiting, rash, pruritus (itching), headache---particular
care should be taken with patients with preexisting neuropathy.
(18) Richardson PG et al. studied 202 patients (pre-treated
with at least 3 prior chemo protocols) with relapsed, refactory myeloma
(seems to be a final report of (16), a 2002 ASCO abstract); PS-341 @
1.3 mg/m2 2X/week (2/3); response = 35%, MDR 12 months, MDS 16 months;
Conclusion: PS-341 is a new class of anticancer drugs, active in
patients with relapsed multiple myeloma that is refactory to conventional
chemotherapy; toxicities: thrombocytopenia (28%-low
platelets), fatigue (12%), peripheral neuropathy (12%),
neutropenia (low WBC) in 12%. (19)
Stevenson J et al. studied 12
minimally treated advanced non-small cell lung cancer patients; PS-341 @ 1.5
mg/m2 as a 5 minute IV infusion on D 1, 4, 8, 11 of a Q21 protocol; 1/8 PR,
2/8 SD; toxicities: peripheral neuropathy (4/12), nausea
(10/12), fatigue (9/12), diarrhea (3/12); Conclusion: PS-341 displays
early evidence of clinical activity in advanced NSCLC with evidence for
reduction in antipoptotic proteins in PMNs of treated patients. (20) Maki
RG et al. are conducting a study with 12 untreated recurrent or
metastatic soft tissue sarcoma patients; PS-341 @ 1.5 mg/m2 IV push 2X/week
(2/3); toxicities: persistent neuropathy , fatigue,; response:
7/11 progression, 1/11 mixed response, 2/11 stable disease; 11/13 patients
are off study; accrual is ongoing (BLA question: why?) (21)
Drucker BJ et al. studied 32 renal cell, cancer patients with PS-341 @
1.5 mg/m2 (decreased to 1.3 mg/m2) 2X/week (2/3); no prior chemotherapy or
peripheral neuropathy; 9% PR, MDR = 1.2 months;
peripheral neuropathy was the most troublesome toxicity. (22)
Aghajanian C et al. studied 9 recurrent ovarian cancer patients; 2
prior chemotherapeutic agents were allowed; PS-341 @ 0.75, 1.0, 1.3, 1.5
mg/m2 D 1, 4, 8, 11 by IV bolus given one hour before Carboplatin
@ 5 AUC on D 1; no neurotoxicity; 7/9 patients have had major responses.
(23) Davis NB reports a strange study of 23 stage IV renal cell cancer;
Q21 PS-341 @ 1.5 mg/m2 2X/week; one objective response; toxicities:
arthralgia (joint pain), diarrhea, vomiting, 9/22 thrombocytopenia
(low platelets), anemia, febrile neuropathy, pain, fatigue, 2/23
neuropathy, electrolyte disturbances, thrombosis, pleural effusion;
Conclusion: there is no evidence for clinically significant activity
of PS-341 in metastatic renal cell cancer. (24)
Roth BJ et al. reported that in preclinical studies the combination
of PS-341 + Taxotere had additive anti-tumor activity without
additive toxicities; they studied 12 patients with advanced
androgen-independent prostate cancer; patients had AIPC with
radiological and/or biochemical evidence of progression following AAWR and
with castrate testosterone levels; Q21 Taxotere @ 25, 30, 35, 40 mg/m2 over
30 minutes on D 1 & 8 + PS-341 was given 24 hours after Taxotere @ 1.3 mg/m2
IV push on D 2 & 9; RR 33%; MTD was not reached; toxicities: diarrhea, and
hyperglycemia (high circulating blood glucose), hyponatremia (low
circulating blood sodium ions), hematuria (blood in the urine), and one
pathological fracture; Conclusion: Taxotere + PS-341 were well
tolerated at these doses and schedule. (25)
Richardson P provided a review of Velcade in hematological
malignancies; in cell culture and xenograph models, PS-341 showed potent
activity, enhanced sensitivity of cancer cells to traditional
chemotherapeutics, and appeared to overcome drug resistance; in vivo
trials, responses are noted with manageable toxicities. (26) Cusack JC
reviewed the rationale for using PS-341 in the treatment of solid
tumors; cell culture and xenograph models data suggest PS-341 may be active
in a wide variety of tumor types; a possible use of PS-341 is the treatment
of chemoresistant tumors; NFkB is a prominent instigator of chemoresistance
and proteasome inhibition is an effective means of preventing NFkB
activation and provide a means to treat refactory tumors. (27) Lenz HJ
reviewed a clinical update of proteasome inhibitors in solid tumors;
PS-341 is the first proteasome inhibitor to have progressed to clinical
trials; through the prevention of IKappaB degradation, PS-341 may block
chemotherapy-induced NFkB activation and augment the apoptotic response to
chemotherapeutic agents; it inhibits tumor growth and demonstrates anti-angiogenic
properties; PS-341 exhibits the greatest activity when combined with
chemotherapeutic agents (irinotecan, Gemzar, Taxotere) suggesting its
potential additive /synergistic role in overcoming resistance to
conventional chemotherapy with manageable toxicities. (28)
CONCLUSION
The preclinical studies of cell cultures and xenograph models
demonstrated that PS-341 (Velcade) can disrupt pathways that are essential
and critical for tumor development and growth. It is a potent and very
selective inhibitor of the proteasome, which plays a critical role in the
cell degrading numerous protein substrates that regulate both the cell cycle
and prosurvival pathways. Proteasome inhibitors were found to be cytotoxic
to a wide variety of cancer cells by inducing apoptosis. It was found to
enhance the efficacy of a variety of chemotherapeutic agents when used in
combination, and to overcome drug resistance; and toxicities were considered
to be mild and manageable.
I do not know the median time-line for a drug to progress from a
laboratory setting through animal testing and finally into human testing.
Many drugs take several years; and clearly Phase 1 trials are just that--
trial and error trying to establish dosing, side-effects, and drug efficacy
in accomplishing the goal of the experiment. But, I am uncomfortable with
what I see as a disconnect between the PS-341 preclinical
declarations/findings and the results of the early trials. If PS-341 is
"selectively cytotoxic to cancer cells and does not affect healthy cells",
why does every trial report significant vomiting, fatigue, diarrhea, nausea,
thrombocytopenia, peripheral neuropathy, etc.? The drug is clearly affecting
healthy cells. Moreover, these early (and, very small cohorts of patients)
certainly do not indicate that these toxicities are "mild and manageable".
Is Velcade our Magic Bullet? Not yet, in my opinion. Is it
exciting and filled with hope as a breakthrough drug for cancer? I think so.
Meanwhile, what is our choice when we have exhausted the conventional agents
and protocols to treat our disease? In my opinion we must seek experimental
drugs in an effort to prolong our survival and hope we can obtain the drug.
And, notwithstanding the low probabilities, we must hope that the drug will
be effective in our particular case.
Bill Aishman
NOTE: I am not a doctor and can not give medical advice. I am a
prostate cancer patient with advanced disease and I performed this layman’s
analysis for my own decision-making purposes. In conjunction with a medical
team, every cancer patient must make their own decisions regarding treatment
options. I make no claim that this analysis is definitive or complete.
REFERENCES
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(2)
http://embryo.ib.amwaw.edu.pl/home/cwojcik/proteas.htm
(3)
http://www.medscape.com/viewprogram/2318
(4) http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Proteasome.html
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(8) Logothetis CJ et al.; Dose
Dependent Inhibition of 20S Proteasome Results in Serium Il-6 and PSA
Decline in Patients with Androgen Independent Prostate Cancer Treated with
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(9) Logothetis' group;
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(22) Drucker BJ et al.; Phase II
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