CANCER BIOLOGY AND INFORMATICS

ASSIGNMENT 1

Name: Saumya S

Reg. No.: 15BBT0054

THERAPEUTIC STRATEGY TO TARGET c-Myc

INTRODUCTION:

Myc (c-Myc) is a regulator gene that codes for a transcription factor. In the human genome,
Myc is located on chromosome 8. The protein encoded by this gene is a multifunctional,
nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis and cellular
transformation.

A mutated version of Myc is found in many cancers, which causes Myc to be constitutively
expressed. This leads to the unregulated expression of many genes, some of which are
involved in cell proliferation, and results in the formation of cancer. A common human
translocation involving Myc is critical to the development of most cases of Burkitt
lymphoma. Malfunctions in Myc have also been found in carcinoma of the cervix, colon,
breast, lung and stomach. Myc is thus viewed as a promising target for anti-cancer drugs.

FUNCTION:

Myc protein is a transcription factor that activates expression of many genes through
binding enhancer box sequences (E-boxes) and recruiting histone acetyltransferases
(HATs).
Myc is activated upon various mitogenic signals such as serum stimulation or by Wnt,
Shh and EGF (via the MAPK/ERK pathway). By modifying the expression of its
target genes, Myc activation results in numerous biological effects.
The first to be discovered was its capability to drive cell proliferation (upregulates
cyclins, downregulates p21), but it also plays a very important role in regulating cell
growth (upregulates ribosomal RNA and proteins), apoptosis (downregulates Bcl-2),
differentiation, and stem cell self-renewal.
Myc is a very strong proto-oncogene and it is very often found to be upregulated in
many types of cancers. Myc overexpression stimulates gene amplification,
presumably through DNA over-replication.
ARGUMENTS AGAINST THERAPEUTIC TARGETING OF Myc:

1. First, Myc is rarely mutated in cancer despite its high level of expression. Exceptions
do occur in Burkitt and AIDS-related lymphomas where approximately 30% of
primary tumors carry amino acid substitutions in Myc.
2. Second, Myc expression is a nearly universal property of all proliferating cells, and its
inhibition might be associated with unacceptable toxicities.
3. Third, Myc inhibitor design will be difficult. The most obvious approachesfor
instance, targeting the association between Myc and Max or other essential cofactors,
involve the disruption of proteinprotein interactions.

ARGUMENTS FOR THERAPEUTIC TARGETING OF Myc:

1. First, despite the general lack of Myc protein mutations, most tumors are Myc
dependent to varying degrees.
2. Second, Myc expression by normal cells might not necessarily limit the use of Myc-
based therapies. At any given time, most normal cells are quiescent and express little,
if any, Myc; thus, they might not be subject to the effects of Myc inhibitors.
3. Third, the notion that proteinprotein interactions might be refractory to small
molecule inhibitors has gradually yielded to experimental evidence to the contrary.
Indeed, that single amino acid substitution in the bHLH-ZIP dimerization domain of
Myc could abolish its interaction with Max.
4. Finally, Myc-based therapeutics relies on a novel molecular target. They should
therefore be compatible and largely non-cross-resistant with many pre-existing
chemotherapeutic agents.

THERAPEUTIC TARGET:

a. Proteosomal degradation of c-Myc:

c-Myc is necessary for the rapid proliferation of cancer cells. Strategies aimed
at targeting c-Myc, including interfering with c-Myc synthesis, stability and
transcriptional activity, have emerged as effective cancer treatments.
It is recently shown that a natural agent, oridonin, promotes the proteasomal
degradation of c-Myc, leading to subsequent cell growth inhibition and
apoptosis and demonstrating a new c-Myc-targeting strategy.
Despite the effectiveness of molecular targeting in cancer treatment, failure to
achieve long-lasting efficacy with a single agent is observed because cancer
cells can recover from oncogene addiction as a result of their genomic
instability and heterogeneity.
Combined cancer therapies were therefore developed and showed better
efficacies than single-agent therapy in cancer cell lines and mouse models.
Agents that also target c-Myc but use different mechanisms, or agents that act
on other genes in the c-Myc pathway, can be selected for combination.
 In addition, the targeting of genes involved in different cellular processes in
other pathways might also be a successful strategy. Regardless of the therapy
adopted, it is important to first determine the molecular mechanisms
underlying the agents to inform the therapy design.

b. Combined targeting agents c-Myc and microRNAs:

Among the various targets of therapeutic agents is a family of non-coding
small RNAs, called microRNAs, which have been implicated in the anti-
cancer activity of many therapeutic agents.
c-Myc, as a transcription factor, regulates the expression of many microRNAs
and is in turn regulated by microRNAs. Combining c-Myc-targeting agents
with those that target microRNAs might provide a novel approach for cancer
therapy.

c. Small-molecule ligands targeting the c-Myc promoter G-quadruplexes:

G-quadruplexes have been shown to be a promising target for anti-cancer
therapy, based on their functions in regulating c-Myc transcription and
suppressing tumorigenicity.
Nuclease hypersensitive element (NHE) III1, a G-rich sequence of c-Myc
promoter, has two different forms, transcriptionally active and silenced forms;
When the G-rich sequence exists in the form of double helix, RNA
polymerases in cooperation with various other factors can transcribe c-Myc
gene.
In contrast, the silenced form, containing G-quadruplexes, prevents the various
transcription factors from interacting with the element, leading to a down-
regulation of c-Myc transcription.
Since G-quadruplexes play important roles in the repression of c-Myc, small-
molecule ligands that can specifically induce the formation of and stabilize the
G-quadruplex in vivo may be developed as promising anti-cancer drugs.

Examples of Molecule ligands:

1. Perylene derivatives: Perylene compounds have been reported to strongly

interact with G-quadruplexes.

2. Cationic porphyrins: It has been proven to down-regulate the expression

level of c-Myc through combining with G-quadruplexs.

3. Alkaloids: From a long-term perspective, natural products have been a

good source of compounds with therapeutic activity and low toxicity in the
development of tumor-selective therapies, of which telomestatin has been
shown to be one of the most potent G-quadruplex ligands.
RECENT CASE STUDY ON TNBC:

Potential therapeutic target discovered for triple negative breast cancer.

a. Expression of the PIM1 protein was elevated in tumor samples from patients with
MYC-positive triple negative breast cancer (TNBC), and was also associated with
poor prognosis in patients.
b. After the inhibition of PIM1, mice showed decreased tumor growth as well as an
increase in cell apoptosis.

CONCLUSION:

c-Myc protein is a transcription factor that activates expression of many genes.

Various targeting therapeutics have been found to suppress the expression of various
genes subject to the transcription factor.
Different targets have been identified that could be a good therapeutic target and
drugs have been developed like small molecule ligands, development of combined
targeting agents and proteosomal degradation.
From the articles that I have read, I could infer that targeting multiple factors at once,
the molecule has improved efficacy and decreased toxicity to the host.
It can also be assured that targeted therapeutics has more effect towards the treatment
process than chemotherapy.

REFERENCES:

http://www.sciencedirect.com/science/article/pii/S0092867411009433

https://www.ncbi.nlm.nih.gov/pubmed/25341931

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995947/

http://www.2minutemedicine.com/potential-therapeutic-target-discovered-for-triple-negative-
breast-cancer-preclinical/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819695/

https://www.biosciencetechnology.com/news/2017/02/potential-new-anti-cancer-drug-class-
inhibits-multiple-molecular-targets
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202025/