Melanoma Molecular Maps Projects

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Molecularly targeted therapy



Melanoma resistance to conventional medical treatments (i.e. radiotherapy and chemotherapy, see Conventional Therapy section) explains the virtual absence of therapeutic options in case of metastatic disease; furthermore, in the adjuvant setting melanoma refractoriness to antineoplastic agents has left clinicians with a single and still controversial therapeutic weapon, that is IFN-alpha. Therefore, the best current therapeutic approach for melanoma is early diagnosis. In the light of these considerations, novel anti-melanoma therapeutic strategies are urgently needed to give new hope to patients affected with this deadly type of cancer.

Most conventional antineoplastic approaches/agents (i.e. chemotherapeutic drugs and radiotherapy) are not tumor-specific and exert their cytotoxic effect mainly on proliferating cells, often relying on small differences in drug sensitivity between tumor cells and normal tissues to deliver a therapeutic benefit. Consequently, they have significant limiting toxicities (narrow therapeutic window/low therapeutic index, i.e. the odds for suffering from treatment-related adverse effects are similar or even superior to the probability of obtaining a clinical benefit) and greatly reduced efficacy against non-proliferating (dormant) or slowly growing (low-mitotic index) malignant cells (which are believed to be responsible for disease recurrence after apparently curative surgery or - much less often - apparently complete response to medical therapy).

Anticancer drug discovery is shifting from an empiric random screening approach to a more rational and mechanistic, target-directed approach, where specific abnormalities in cell functioning are modulated in a classical drug-receptor fashion [1]. Drugs targeting tumor specific pathways can be not only more effective but also less toxic. Recent clinical trials (including many randomized controlled trials, RCT) have demonstrated the therapeutic potential of such molecularly targeted agents against some tumors such as breast, colorectal, lung and renal cell carcinomas, chronic myeloid leukemia, and gastrointestinal stromal tumors (GIST) [2, 3].

Molecularly targeted anticancer therapy is based upon two main approaches, which should not be considered separately but rather in combination, with the aim to capitalize on their synergistic therapeutic effect:

A)

The development of drugs or therapeutic strategies targeting tumor specific molecular derangements. Examples of this approach are the following:

- molecularly targeted agents (e.g. small molecule inhibitors of tyrosine kinase receptors), antibodies targeting key tumor survival/progression factors (e.g. EGFR, VEGF)

- gene therapy: use of genetic material to recover the function of tumor suppressor genes lost during cancer development/progression or to inhibit the function of oncogenes (over)expressed by tumors (e.g. antisense oligonucleotides, small interfering RNA)

- specific immunotherapy: active (anticancer vaccines) and passive (cytotoxic antibodies) immunotherapeutic approaches

B)

The identification of biomarkers (or molecular profiles) with prognostic value (e.g. able to identify patients who need adjuvant therapy because of the persistence of minimal residual disease [MRD]) and or predictive value (e.g. able to identify the patients who best benefit from a traditional or molecularly targeted therapeutic regimen).

This therapy-oriented molecular approach to cancer medicine requires a tight cooperation and intense exchange of knowledge between clinicians and basic researchers, a concept that has been recently developed and has reached the autonomous dignity of a discipline, called "translational medicine" [4].

Although targeted therapy is at an earlier stage of clinical implementation in the case of melanoma, the (still partial) elucidation of the cascade of molecular events underlying melanoma development and progression is fostering the interest of investigators in this field [5-14].

The systematic, rationally organized, and continuously updated collection of the translational medicine findings on melanoma is one of the main aims of the MMMP website.


References

[1] Sawyers C, Targeted cancer therapy. Nature 2004, 432: 294-7

[2] Adams GP et al, Monoclonal antibody therapy of cancer. Nat Biotechnol 2005, 23:1147-57

[3] Krause DS et al, Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005, 353:172-87

[4] Marincola FM, Translational medicine: a two-way road. J Transl Med 2003, 1:1

[5] Chudnovsky Y et al, Melanoma genetics and the development of rational therapeutics.J Clin Invest 2005, 115:813-24

[6] Herlyn M, Molecular targets in melanoma: strategies and challenges for diagnosis and therapy. Int J Cancer 2006, 118:523-6

[7] Kabbarah O et al, Revealing the genomic heterogeneity of melanoma. Cancer Cell 2005, 8:439-41

[8] Green CL et al, Targets for molecular therapy of skin cancer. Semin Cancer Biol 2004, 14:63-9

[9] Sosman JA et al, Molecular targets in melanoma from angiogenesis to apoptosis. Clin Cancer Res 2006, 12:2376s-2383s

[10] Gray-Schopfer V et al, Melanoma biology and new targeted therapy. Nature 2007, 445:851-7.

[11] Lejeune FJ et al, New approaches in metastatic melanoma: biological and molecular targeted therapies. Expert Rev Anticancer Ther 2007, 7:701-13.

[12] Hocker TL et al, Melanoma genetics and therapeutic approaches in the 21st century: moving from the benchside to the bedside. J Invest Dermatol 2008, 128:2575-95.

[13] Lorigan P et al, Systemic therapy for metastatic malignant melanoma--from deeply disappointing to bright future? Exp Dermatol 2008, 17:383-94.

[14] Triozzi PL et al, Targeted therapy for uveal melanoma. Cancer Treat Rev 2008, 34:247-58.

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