In the summer of 1966 the Beach Boys and the Beatles topped the popular music charts, the nowclassic television show Star Trek first aired, and a young physician-scientist
by the name of George Lipkin filed for an National Cancer Institute grant to
study melanoma. He held the belief that melanoma could actually be a reversible
disease. This was considered quite a radical idea at that time and Dr. Lipkin
had never received his own grant before. Nevertheless, the grant was awarded
and a lifelong pursuit was underway. This work became the foundation of Biomega Laboratories, Inc. (“Biomega”), a company devoted to development of a substance
that might just make that original idea a reality.
Not a lot was known at that time
about the biological characteristics
that distinguished cancer from normal cells. Dr. Lipkin began by
transfecting hamster melanoma cells (melanoma is malignancy in thepigment producing cells of the skin) with DNA or RNA from blue nevi. Blue
nevi are heavily pigmented, benign cells that most people would recognize as
birthmarks. Although the next three years were mainly spent optimizing the
methods for transfection of the DNA
or RNA, the results seemed to justify
the effort. Dr. Lipkin was able to reintroduce pigmentation to non-pigmented
melanoma cells. Even more encouraging, these
same cells displayed a 400 % decrease in their growth rate, making them more
like normal skin cells. He also discovered melanoma cells that did not
reacquire the ability to produce pigmentation but behaved like normal
melanocytes in another very important way.
Normal cells exhibit contact
inhibition - they cease to grow or divide any further once they encounter
another cell. Malignant cells no longer display
this behavior. Fortuitously, during one transfection experiment, Dr. Lipkin came
upon a non-pigmented cell line thatcontinued to display contact inhibition. These new cells became the
subject of his studies for the next several years, but they failed to reveal
the agent conferring contact inhibition. However, a break-through would occur
during a sabbatical in Switzerland.
While working in a laboratory at the Abteilung für Krebsforschlung, in
Zurich, Dr. Lipkin decided to try
somethingvery different. He took a
sample of the medium that bathed this new
cell line and added it to a fresh culture of hamster malignant melanoma cells.
Within 48 hours these cells also began to exhibit contact inhibition and more
normal growth. What he had witnessed was the passive transfer of contact
inhibition by an unknown element found in the media of the transfected hamster
melanoma cells. This element was named “Contact Inhibitory Factor”, or “CIF™”.
Upon exposure to hamster cell-derived CIF, contact inhibition and
“normalization of growth” was also apparent in a wide
variety of human, mouse and rat
cancer cell lines including melanoma, colon carcinoma, neuroblastoma,
neurinoma, glioma, mammary carcinoma, rhabdomyosarcoma, prostate carcinoma, lung carcinoma, and several other solid tumors.
Upon his return from Zurich Dr. Lipkin, then joined by Dr. Martin Rosenberg, conducted further in vitro experiments.
They demonstrated that CIF restores
the three main analoguesof normalin vivo growth to cancer cells. In addition to
density dependent growth, or contact
inhibition, the cells also displayed serum dependent growth and anchorage dependent
growth. Microscopic examination of
theCIF treated cells revealed a morenormal appearing
important for normal cell signaling and growth regulation.
In order to determine CIF’s effectiveness in vivo, hamster melanomas were implanted subcutaneously
into hamsters and a formulation of partially purified CIF injected twice
weekly around the tumor. Despite the termination of treatment after 30 days,
the tumors began to recede, eventually disappearing. While all of the control hamsters perished by week 9 with massive tumors, the CIF-treated
hamsters lived full life spans with
no evidenceof cancer. Pathology showed only the presence of necrotic tissue where the tumor had been with no evidence of overt local or systemic toxicity.
A similar experiment done in
mice with implanted Lewis lung carcinoma led to regression in 75 % of tumors after only
10 days of CIF treatment. Only fluid and necrotic debris remained at the site
of the tumors.
These in vitro and
in vivo experiments suggested that Dr. Lipkin had
discovered an endogenous and
apparently non-toxic factor that restores normalgrowth
controls to cancer cells and causes
permanent regression of tumors.
Furthermore, itseffects were neither species nor tissue specific. His focus then turned towards
understanding the mechanisms behind these effects. Dr. Lipkin thought thatthe first clue might lie in
surveil-lance. Whereas cancer cells will often go undetected by the
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defenses, reversion of the malignant phenotype by CIF led to an increased immune response inboth humoral and cellular arms. Increased expression of class I
Major Histocompatability Complex antigens made the tumor cells more susceptible to detection and destruction by
cytotoxic T lymphocytes. In melanoma cells CIF also inducedthe
expression of pigmentation antigens that have been shown to enhance antibody-dependent
CIF also displays anti-angiogenic
activity, interfering withthe creation
of new blood vesselsthat may have served a progressing tumor.In vitro, CIF almost completely shuts down the ability
of melanoma cells to secrete VEGF, a common angiogenic factor. At the same time, CIF inhibits
response of blood vessel endothelial cells to another angiogenic factor, ßFGF.
Finally, data provided by a chick embryo model suggested that CIF might
interfere with metastasis as well.
Laboratories Inc. wasincorporated in 1999 with the expressed purpose of bringingCIF to
market for the treatmentof cancer. Currently the companyhas
three members on its team -its two scientific founders, Dr.George Lipkin and Dr.
MartinRosenberg (both are faculty atNYU) and Dr. Richard Glaser,the company’s chief executive officer. Biomega supports the effort to investigate and
developCIF as a therapeutic candidatethrough the work carried out inDr. Lipkin’s laboratory as well as collaborations with other groups both within and outsideof NYU. One of the most recent and
important results of these collaborations has been the isolation and
characterization of the single, active
constituent of CIF. In addition to seed funding by angel investors, the company has been awarded a NYSTAR grant.
In regard to the future, Drs. Lipkin and Rosenberg believe that given the animal and in vitro data collected thus far (Table 1) CIF may be effectiveagainst a wide variety of cancers.
Other possible markets for CIF are ophthalmology (diabetic retinopathy, macular degeneration due to aging), dermatology (psoriasis) and the research
laboratory. But the first indication will most likely be for malignant melanoma. This disease is the seventh most
common cancer in the U.S. and the most common among women ages 25-29. Response
rates with currently available therapies are only 20 %. The company believes
that this makes it an
ideal candidate forFast Track approval by the FDA.
will die of cancer in 2004. That’s nearly
twice the number of victims reported in 1966, when Dr. Lipkin began to think
about a new therapeutic approach.