Learn about Theradiag and microRNAs

n°4 - March 2016

Find the poster of Theradiag published on the occasion of the European AIDS Conference (EAC) 2015, showing the know-how of its microRNA platform, Prestizia. This poster illustrates the R&D of Prestizia on the HIV field. (See)

For the miCRA project development in the rectal cancer, Theradiag has signed two partnership agreements with the CHU of Bordeaux and UNICANCER. Theradiag will have access to a total of 440 samples thanks to the two clinical trials GRECCAR 12 and PRODIGE 23. These samples will enable Theradiag to perform the biological validation of two microRNAs signatures in the rectal cancer. (See)

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Theradiag presents at JFHOD the results of a microRNAs signature predicting a patient’s therapeutic response in locally advanced rectal cancer (See the poster). - Identification conducted as part of the miCRA project, in conjunction with the Regional Cancer Institute of Montpellier (ICM) - Results presented at the JFHOD (Francophone Gastroenterology, Liver-Disease and Digestive Cancer) congress Find the summary of the poster on page 4.

Find in this edition

News P1

Expert testimonies

- Pr Glimelius, Uppsala University P2

- Dr Nougaret, CHU of Montpellier P3

Scientific reviews on microRNAs P4

Develop innovative tools

that meet major unsatisfied clinical needs

Use microRNAs as predictive biomarkers

of the response to treatment and the monitoring of the patient

Make personalized medicine a reality

for the clinician and his patient Challenges

Mission

Strategy

Latest news about our microRNA platform

JFHOD

17-20 march

Palais des congrès, Paris

Booth 14b

In spite of many and large conclusive trials, therapy for rectal

cancer varies widely worldwide.

We have learned a lot about how to treat rectal cancer patients

for cure, to avoid a disabling local recurrence, to reach high

curability rates and to minimize morbidity from treatments. The

interpretation of the trial results differs however worldwide.

Everybody can agree that treatment for early tumours can be

surgery alone and for the most advanced tumours pretreatment

is required prior to surgery. Controversies exist for the great

majority of tumours intermediate between those two extremes.

In Sweden, following the ESMO guidelines, rectal cancers are

divided into three groups, early, intermediate and locally

advanced. In daily clinical work they are often designated good,

bad and ugly.

In early tumours, the risk of a local recurrence is so small that

surgery alone is adequate. These tumours constitute some 40% of

all rectal cancers. After high quality staging MRI, early tumours

are cT1-2 and possibly cT3a if within the first 5 cm from the anal

verge, up to cT3b in middle rectum and up to cT3c in upper

rectum provided the mesorectal fascia (mrf) is not threatened.

Lymph node status is less relevant, but if pathological nodes are

present they should be not more than one or two in upper

rectum. The intermediate group constitutes tumours where the

local recurrence rate after surgery alone is higher and it is

motivated to decrease the risk by about 60% with preoperative

radiotherapy. Most cT3 tumours belong to this group and some

T4a. The best documented treatment for these tumours is short-

course radiotherapy (5x5 Gy), convenient, less costly and with

much less toxicity than chemoradiotherapy to about 50 Gy with

capecitabine. These tumours constitute about 45-50% of all rectal

cancers. In locally advanced or ugly tumours, basically cT3 mrf+

and cT4b growing towards a difficult-to-resect organ requires

down-sizing and/or down-staging and it is not appropriate to

operate immediately. For these tumours, constituting only some

10-15% of all rectal cancers, chemoradiotherapy is best

documented. In very old patients and in patients with

comorbidity, short-course radiotherapy with a delay of 6-8 weeks

is an attractive and likely as efficient alternative.

In most of the world, the intermediate and locally advanced

rectal cancers are called “locally advanced” meaning that far too

many patients are treated too intensively with

chemoradiotherapy.

There are several remaining issues in rectal cancer therapy. One

is to delay surgery after short-course radiotherapy. Complications

after surgery are then less, down-staging and down-sizing are

seen and sometimes also a complete clinical and pathological

response. A disadvantage may be that the start of adjuvant

chemotherapy is postponed. After release of the first results from

the Stockholm III trial, comparing short-course radiotherapy with

immediate or delayed surgery and long-course radiotherapy with

delayed surgery, short-course radiotherapy with a delay has

become increasingly popular.

Organ preservation is presently enormously popular and can be a

valuable option in selected patients, particularly since surgery

even in the absence of a permanent stoma causes quite some

morbidity. Organ preservation depends upon sensitivity to

radiation or chemoradiation and presently, this cannot be

predicted besides tumour size. A small tumour, likely an early

tumour has a higher probability to respond than a large or locally

advanced tumour, even if a very low-lying tumour can be locally

advanced even if small.

The greatest challenge is still to improve survival.

Adjuvant chemotherapy in rectal cancer is used extensively, but

the scientific evidence for benefit is limited and likely, the

beneficial effect on survival is at best marginal. The use of neo-

adjuvant chemotherapy in patients with high risk of systemic

failure is presently explored in randomized trials, for example in

the Dutch/Swedish randomized RAPIDO study. The study

randomizes the most advanced intermediate cancers and the

locally advanced tumours into the reference treatment

chemoradiotherapy, surgery and optionally adjuvant

chemotherapy (8 cycles of XELOX) versus short-course

radiotherapy, neo-adjuvant chemotherapy (six cycles of XELOX)

and finally surgery. Over 800 patients have so far been

randomized.

2

Dept. of

immunology,

genetic and pathologies

Uppsala

university

Expert opinion

Rectal cancer radiotherapy

Pr Bengt

GLIMELIUS

Attempts to organ preservation must rely on abilities to predict

sensitivity to (chemo)radiotherapy unless far too many patients

will be treated too extensively.

The backside of an upfront organ preservation strategy, namely

that many patients with early tumours will have both the

morbidity from chemoradiotherapy and from surgery because

they did not reach a durable complete clinical remission.

That backside for many patients must then be balanced against

the advantage of avoiding surgery for some. To go for organ

preservation in a patient whose tumour respond with a complete

clinical remission who otherwise needed pre-treatment to have a

reasonable chance of local control is much less controversial,

although care should still be present in very large tumours (above

5-6 cm in largest diameter). They may respond well, but often

recur.

Colo-Rectal Cancer is the third most commonly diagnosed cancer

in males and the second in females. Around 30% of all colorectal

cancers are diagnosed in the rectum. Despite the major

improvements that have been made management of rectal

cancer still remains a challenge.

Chemoradiotherapy (CRT) followed by surgery has been widely

adopted for the management of locally advanced rectal cancers

because this approach increases the probability of anal sphincter

preservation, decreases the local recurrence rate and decreased

the risk of colostomy. As we enter the era of personalized

medicine with therapies stratified according to the risk of local

or distant recurrence, imaging has become an essential tool in

the preoperative decision making, to avoid both under- and

overtreatment. This requires a full understanding of the disease,

as well as a full understanding of what impact false- positive or

false-negative findings can have on treatment choices and

outcome. The role of magnetic resonance imaging (MRI) in rectal

cancer is well established, and it is now part of the standard

work-up in many countries.

MR imaging, like other morphologic imaging techniques is

hampered by interpretation difficulties in assessing the presence

of residual tumor within areas of radiation-induced fibrosis.

« The development of miCRA project is a challenging but a

critically needed project. »

Therefore, new biomarkers focusing on functional and/or

quantitative methods have been evaluated such as tumor

volumetry, MRI tumor regression grade and diffusion weighted

imaging. Validation of these new biomarkers and their eventual

incorporation into clinical practice holds promise for improved

cancer treatment.

In the mean time, revolutionary advances in molecular biology,

biomedical imaging and information technology have opened up

new avenues towards molecularly-based, "precision medicine,"

in which treatments are tailored to the specific biological

features of disease in the individual patient. To date, there are

no molecular decision-making tools available to predict the

efficacy of the pre-operative CRT or metastatic relapse in rectal

cancer.

The development of miCRA project is a challenging but a

critically needed project. Indeed, it could enable the

identification of circulating miRNAs signature predictive of

patient response to treatment or relapse. Setting up these

decision-making tools would help carry out personalized

surgeries and post-operative treatments. However, we know

that tissue and serum assays alone cannot sufficiently capture

the spatial and temporal diversity of tumor biology and spatially

localized, imaging of the disease will still remain essential. Thus,

with the development of miCRA project, we are just a step away

to bring imaging and molecular biology together. This could soon

represent a new combined biomarker to accurately predict

rectal cancer tumor response.

Department of

radiology

CHU of Montpellier

Dr Stéphanie

NOUGARET

3

Biomarkers at the service of MRI

« A Five-miRNA Panel Identified from a Multicentric Case–control Study Serves as a Novel Diagnostic Tool for Ethnically Diverse Non-small-cell Lung Cancer Patients. » Cheng W. et al. EBioMedicine . October 2015.

Cervix cancer is one of the main causes of mortality in

women. Results of this study identified a microRNA signature

which can predict the clinical course of cervix cancer. Indeed,

overexpression of microRNA 21 is associated with an

aggressive progression and a poor prognosis of cervix cancer.

These promising results could lead to a better care of cervix

cancer. (Read)

Lung cancer remains the most lethal cancer due to a late

diagnostic. A multicentric and multi-ethnic study highlighted a

signature of five serum microRNAs. This combination allows

the diagnosis of the non-small cell lung cancer (NSCLC) at an

early stage and thus better anticipate it. This signature allows

an effective detection of NSCLC during stages I and II.

This results suggest that this signature could be a useful

biomarker for diagnosis of NSCLC in patients of all ethnic

origins and thus allowing an early care of patients with NSCLC

to improve survival. (Read).

« Dysregulation of miRNA-21 and their potential

as biomarkers for the diagnosis of cervical

cancer. »

Han Y et al. Int J Clin Exp Pathol . June 2015.

Type 1 diabetes is an autoimmune disease causing pancreas cells self-destruction and leading to insulin production stop. This disease

is currently detected once the first symptoms appear, damages having started a few years before. So far no microRNA associated to

this pathology has been identified but recent studies have shown that the microRNA 375 secreted by cells producing insulin, is

released in blood in larger quantities at the onset of type 1 diabetes. This biomarker could help physicians to diagnose the disease at

an earlier stage. Authors have planned to validate the use of this new marker as an early detection factor of type 1 diabetes.

(Read)

« miR-375 gene dosage in pancreatic β-cells: implications for regulation of β-cell mass and biomarker development. »

Latreille M. et al. Journal of Molecular Medicine. May 2015.

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« Identification d’une signature de miARN sériques prédictifs de la réponse au traitement néo-adjuvant dans les cancers du rectum localement avancés » E. Crapez et al. JFHOD. March 2016

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Today, the neoadjuvant chemoradiotherapy (CRT) is the

reference treatment for locally advanced rectal cancers.

However, there is significant inter-subject variability in

patient response to CRT and so far no specific biomarker has

been validated in this situation. To help clinicians to predict

response to CRT, we have identified a microRNAs signature.

A study has indeed been carried out on 69 patients with

rectal tumors T3-T4 and/or N+ traited by a CRT. According to

the Dworak classification, 34 patients were responders while

35 were non-responders. Blood samples were collected

before any treatment and helped to determine a

combination of 8 miRNAs predictive of the response to the

CRT. Thereafter, a classifier was generated enabling specific

prediction to CRT response on patients with locally advanced

rectal cancers with an AUC of 0.882. The biological validation

of the performances of the signature is under evaluation and

performed with samples from retrospective and prospective

cohorts. Such microRNAs signature should allow

henceforward to predict in a reliable and non-invasive

manner the patient response to CRT. (Read)