Tuesday, June 12, 2012

T-DM1 and Breast Cancer

Fewer agents raise my eyebrow now that every new cancer drugs is labeled as some form of a “nib” or a “mab.” All such categories of targeted antibody to a defined mutated receptor, an epigenetic related loss or gain of function of a gene, or specific protein product of a gene-gone-haywire therapy assault the surface antigen of the cell where the “nib” or “mab” meet the  cell and prevent the flow of a signal from reaching the nucleus (interior) of the cell and thus preventing its (the cells) reduplication.

 Cellular Internalization of the T-DM1 molecule

Signal Transduction:

The signal, you see, is the message from the outside (the exterior of the cell wall) that tells the interior (nuclear) machinery to go into action and replicate another one like itself. On the other hand, the unmitigated growth of the cancer cell is reliant on promoting that signal in a loop mechanism and by virtue of that and the multiple transduction pathways, this leads to the constant barrage of signals to the nucleus giving the continuous directive to grow.

The intracellular communication:

Consider a branching railway line all merging into a single line as so happens at Railway Junctions. If one line goes bad at the junction, it can be piggy-backed/connected to another track or at the station the  passengers can board another train that can be programmed for similar destination. But once the rail lines merge into one, there is only one way out of the station. We are inching our way to disrupting that single railway line. 

At present disrupting the pre-merged railway lines just invites the train to take another line enroute to the common outbound line. That is the reason for the many targeted therapies to have a moment of success in sunshine with cancer but they ultimately fail to maintain the momentum


So what caught my eye was this new drug called T-DM1. Fascinating name to begin with, this drug inspired a closer look. The “T” in the T-DM1 stands for the Trastuzumab as in Herceptin.  Trastuzumab is directed at the HER 2 receptors (The surface antigens I mentioned earlier) present on the breast and various other cancer cells.  So this drug interferes with the signal from the surface (mediated via the HER-2 receptor) to the interior of the cell, required for the cancer cells to grow. The hitch in some cases is the absence of over expression of these receptors on the cancer cell surface of the HER 2 or  the Trastuzumab (Monoclonal antibody to HER 2) cannot collocate to the HER-2 receptor to get internalized and therefore becomes impotent in its action to subvert the HER-2 function from generating the signal.

A (very) Few of the Pathways (Medscape)

Additionally,  another mechanism for failure is the cross-talk between the pathways (interconnecting tracks at the railway junction) merge to allow the signal to be redirected to the interior of the cell via another pathway and once message is delivered, the cancer cell resumes its wayward growth (this then also represents the time delay garnered as "Response" to the targeted therapy followed by failure).

You might ask, why did the body do this multiple pathway “train-station” business inside the cell and make it so difficult to treat? The reason being that these receptors are needed for the growth of the normal cells, but in the normal cells the growth is limited to the need and once that need is satisfied, everything goes back to the quiescent phase of “wait and watch” demand. In cancer, the cells acquire this innate ability to keep themselves in business of growth, (a constant state of demand) much like a politician always promising.

Cancer Cell

So we now get down to the DM1 part. And here is where the real science behind this drug may be transformational. You see back in the late 1900s, there was a drug called Myatansinoid antimicrotubular agent or DM1((N2′-deacetyl-N2′-(3-mercapto-1-oxopropyl)-maytansine C35H48ClN3O10S). DM1 is a derivative of the natural microbial fermentation product and extraordinarily potent antimicrotubule agent ansamitocin P-3.4  It was first studied back in the 1970s.

T-DM1 attached to HER2 Receptor on Cell Surface

The Chemistry behind:

Chemical derivatization of maytansine resulted in the synthesis of a maytansine derivative DM1, which is three- to 10-fold more potent than maytansine, with an inhibitory concentration (IC50) in the picomolar range and broad cytotoxic activity against a wide range of human cancers. Maytansine, although active at extremely low concentrations, exhibited too narrow a therapeutic safety margin, with significant and sometimes unpredictable gastrointestinal toxic side effects that prevented further clinical development. The mode of action determined at that time was that the cleavage between T and DM1 occurs intra-cellularly and also in the plasma, resulting in the progressive depletion of DM1 molecules eventually yielding the individual components of unconjugated antibody and “free” DM1.

Mertansine is linked via a complicated structure – 4-(3-mercapto-2,5-dioxo-1-pyrrolidinylmethyl)-cylohexanecarboxylic acid or MCC –, in which case the International Nonproprietary Name of the conjugate is formed with emtansine as in T-DM1.

Antibody Drug Conjugate (ADC):

So T-DM1 is an "Antiibody Drug Conjugate" (ADC) between the Trastuzumab (Herceptin) and the DM1. The idea behind this immuno-conjugate (ADC) is that the Trastuzumab is attracted to the HER-2 receptor on the cell surface and binds with it. The Trastuzumab is “swallowed” (internalized) into the cell cytoplasm where the delinking between the Trastuzumab and the DM1 occur and then the DM1 is free to play its role of arresting cell division via the microtubulin assembly (An assembly of microtubules that anchor at polar opposites of a dividing cell to "pull" 50% of the nuclear pieces to form "baby cells") and thus rendering it to “programmed cell death” or apoptosis. “The trastuzumab moiety of this ADC binds to HER2 on tumor cell surface surfaces; upon internalization, the DM1 moiety is released and binds to tubulin, thereby disrupting microtubule assembly/disassembly dynamics and inhibiting cell division and the proliferation of cancer cells that overexpress HER2.”


The benefits of T-DM1 were determined from the EMELIA trial that suggest a Progression Free Survival (PFS) in the T-DM1 group of patients compared with the therapy regimen of Capecitabine and Lapatinib.  The translated benefit is 3.2 months (9.6 vs 6.4 months). Median overall survival for patients treated with T-DM1 was not reached, but median overall survival for those treated with standard therapy was 23.3 months (hazard ratio [HR], 0.621; P = .0005)”. Although this does not seem so grand in scale, these patients have been pretreated significantly before, prior to being accrued in this study and that is what gives some solace to the drug designers and those caring for cancer patients and hopefully, down the line, to the patient’s and their families.

In the EMELIA trial  a total of 978 patients in the cohort received treatment. The median durations of follow-up were 12.9 months in the T-DM1 group and 12.4 months in the standard-therapy group. The baseline demographics, previous therapy, and disease characteristics were balanced between the 2 groups.”

Standard Therapy
Overall Survival at 1 Year, %
Overall Survival at 2 Years, %
Objective Response Rate, Months (95% CI)
43.6 (38.6–48.6)
30.8 (26.3–35.7)
Duration of Response in Patients
With Overall Response, Months
Adverse Events of Grade 3 or Higher, %

The drug is by no means a one of a kind. The immuno-conjugations (ADCs) have been created previously between DM1 and other “mabs;” Bivatuzumab, Cantuzumab and Lorvutuzumab. The fact that the benefit is modest with lowered toxicity gives a whole new meaning to immuno-conjugation and the future of cancer therapy.

Oh and if you are forward thinking, you might ask can this be used in early stage cancer as adjuvant therapy? And the answer is why yes of course, as long as future studies continue to sho robust responses. Why that is how all medications are first tried in advanced stage disease and then showing benefit, they are tailored back in the adjuvant (read preventative) settings.

Will the FDA approve T-DM1? It is not a question of if but when.

So now we know of what is to come in the future.

Chari RV, Martell BA, Gross JL, et al: Immunoconjugates containing novel maytansinoids: Promising anticancer drugs. Cancer Res 52:127–131, 1992

Chabner BA, Levine AS, Johnson BL, et al: Initial clinical trials of maytansine, an antitumor plant alkaloid. Cancer Treat Rep 62:429–433, 1978

Blum RH, Kahlert T: Maytansine: A phase I study of an ansa macrolide with antitumor activity. Cancer Treat Rep 62:435–438, 1978

Cabanillas F, Rodriguez V, Hall SW, et al: Phase I study of maytansine using a 3-day schedule. Cancer Treat Rep 62:425–428, 1978

Eagan RT, Ingle JN, Rubin J, et al: Early clinical study of an intermittent schedule for maytansine (NSC-153858): Brief communication. J Nat Cancer Inst 60:93–96, 1978

Issell BF, Crooke ST: Maytansine. Cancer Treat Rev 5:199–207, 1978

2012 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract LBA1.

No comments:

Post a Comment